Piperidine substituted pyrazolo[1,5-a]pyrimidine derivatives with inhibitory activity on the replication of the respiratory syncytial virus (rsv)

ABSTRACT

The invention concerns novel substituted bicyclic pyrazolo pyrimidine compounds of formula (I) having antiviral activity, in particular, having an inhibitory activity on the replication of the respiratory syncytial virus (RSV). The invention further concerns the preparation of such novel compounds, compositions comprising these compounds, and the compounds for use in the treatment of respiratory syncytial virus infection.

FIELD OF THE INVENTION

The invention concerns novel substituted bicyclic pyrazolo pyrimidinecompounds having antiviral activity, in particular, having an inhibitoryactivity on the replication of the respiratory syncytial virus (RSV).The invention further concerns the preparation of such novel compounds,compositions comprising these compounds, and the compounds for use inthe treatment of respiratory syncytial virus infection.

BACKGROUND

Human RSV or Respiratory Syncytial Virus is a large RNA virus, member ofthe family of Paramyxoviridae, subfamily pneumoviridae together withbovine RSV virus. Human RSV is responsible for a spectrum of respiratorytract diseases in people of all ages throughout the world. It is themajor cause of lower respiratory tract illness during infancy andchildhood. Over half of all infants encounter RSV in their first year oflife, and almost all within their first two years. The infection inyoung children can cause lung damage that persists for years and maycontribute to chronic lung disease in later life (chronic wheezing,asthma). Older children and adults often suffer from a (bad) common coldupon RSV infection. In old age, susceptibility again increases, and RSVhas been implicated in a number of outbreaks of pneumonia in the agedresulting in significant mortality.

Infection with a virus from a given subgroup does not protect against asubsequent infection with an RSV isolate from the same subgroup in thefollowing winter season. Re-infection with RSV is thus common, despitethe existence of only two subtypes, A and B.

Today only three drugs have been approved for use against RSV infection.A first one is ribavirin, a nucleoside analogue that provides an aerosoltreatment for serious RSV infection in hospitalized children. Theaerosol route of administration, the toxicity (risk of teratogenicity),the cost and the highly variable efficacy limit its use. The other twodrugs, RespiGam® (RSV-IG) and Synagis® (palivizumab), polyclonal andmonoclonal antibody immunostimulants, are intended to be used in apreventive way. Both are very expensive, and require parenteraladministration.

Other attempts to develop a safe and effective RSV vaccine have all metwith failure thus far. Inactivated vaccines failed to protect againstdisease, and in fact in some cases enhanced disease during subsequentinfection. Life attenuated vaccines have been tried with limitedsuccess. Clearly there is a need for an efficacious non-toxic and easyto administer drug against RSV replication. It would be particularlypreferred to provide drugs against RSV replication that could beadministered perorally.

Compounds that exhibit anti-RSV activity are disclosed inWO-2011/163518, WO-2013/096681 and WO-2013/158776.

SUMMARY OF THE INVENTION

The present invention relates to a compound of formula (I), includingany stereochemically isomeric form thereof, wherein

-   R¹ is hydrogen, hydroxy, C₁₋₄alkyl, mono- or di(C₁₋₄alkyl)amino, or    Heterocyclyl¹;-   R² is hydrogen or C₁₋₄alkyl;-   R³ is C₁₋₄alkyl, halo, C₃₋₆cycloalkyl, mono- or di(C₁₋₄alkyl)amino,    or Heterocyclyl²;-   R⁴ is hydrogen, C₁₋₆alkyl, hydroxy, or halo;-   Heterocyclyl¹ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,    or morpholinyl; wherein each Heterocyclyl¹ is optionally substituted    with one or two substituents selected from C₁₋₄alkyl, hydroxy, halo,    polyhaloC₁₋₄alkyl, C₁₋₄alkyloxycarbonyl, amino,    C₁₋₄alkylaminocarbonyl, or C₁₋₄alkylsulfonyl;-   Heterocyclyl² is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,    or morpholinyl; wherein each Heterocyclyl² is optionally substituted    with one or two substituents selected from C₁₋₄alkyl, hydroxy, halo,    polyhaloC₁₋₄alkyl, C₁₋₄alkyloxycarbonyl, amino,    C₁₋₄alkyloxycarbonylamino, or C₁₋₄alkylsulfonyl;    Het is selected from furanyl, thiophenyl, pyrazolyl, oxazolyl,    thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl,    isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl,    1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl,    1,8-naphthyridinyl, pyrido[2,3-d]pyrimidinyl,    pyrido[3,2-d]pyrimidinyl, 9H-purinyl, thiazolo[5,4-d]pyrimidinyl,    7H-pyrrolo[2,3-d]pyrimidinyl, oxazolo[5,4-d]pyrimidinyl,    thieno[2,3-d]pyrimidinyl, or thieno[3,2-d]pyrimidinyl; wherein each    Het is optionally substituted with one, two or three substitutents    each independently selected from halo, C₁₋₄alkyl, C₁₋₄alkyloxy,    C₁₋₄alkylthio, hydroxy, amino, mono- or di(C₁₋₄alkyl)amino,    hydroxycarbonyl, C₁₋₄alkyloxycarbonyl, C₁₋₄alkylsulfonylamino,    aminocarbonyl, trifluoromethyl, C₁₋₄alkyloxycarbonylamino,    di(C₁₋₄alkyloxycarbonyl)amino, C₁₋₄alkylsulfonylaminocarbonyl,    C₁₋₄alkylamino carbonyl, C₁₋₄alkyloxyC₁₋₆alkyl-oxycarbonylamino,    di(C₁₋₄alkyl)aminosulfonylaminocarbonyl,    C₃₋₆cycloalkyl-sulfonylaminocarbonyl, HO—NH—(C═NH)—; oxazolyl or    triazolyl each optionally substituted with one or two C₁₋₄alkyl;    or a pharmaceutically acceptable acid addition salt thereof.

As used in the foregoing definitions:

-   -   halo is generic to fluoro, chloro, bromo and iodo;    -   C₁₋₄alkyl defines straight and branched chain saturated        hydrocarbon radicals having from 1 to 4 carbon atoms such as,        for example, methyl, ethyl, propyl, butyl, 1-methyl-ethyl,        2-methylpropyl and the like;    -   C₁₋₆alkyl is meant to include C₁₋₄alkyl and the higher        homologues thereof having 5 or 6 carbon atoms, such as, for        example, 2-methylbutyl, pentyl, hexyl and the like;    -   C₃₋₆cycloalkyl is generic to cyclopropyl, cyclobutyl,        cyclopentyl, and cyclohexyl;    -   polyhaloC₁₋₄alkyl is defined as polyhalosubstituted C₁₋₄alkyl,        in particular C₁₋₄alkyl (as hereinabove defined) substituted        with 2 to 6 halogen atoms such as difluoromethyl,        trifluoromethyl, trifluoroethyl, and the like.

The term “compounds of the invention” as used herein, is meant toinclude the compounds of formula (I), and the salts and solvatesthereof.

As used herein, any chemical formula with bonds shown only as solidlines and not as solid wedged or hashed wedged bonds, or otherwiseindicated as having a particular configuration (e.g. R, S) around one ormore atoms, contemplates each possible stereoisomer, or mixture of twoor more stereoisomers.

Hereinbefore and hereinafter, the terms “compound of formula (I)” and“intermediates of synthesis of formula (I)” are meant to include thestereoisomers thereof and the tautomeric forms thereof.

The terms “stereoisomers”, “stereoisomeric forms” or “stereochemicallyisomeric forms” hereinbefore or hereinafter are used interchangeably.

The invention includes all stereoisomers of the compounds of theinvention either as a pure stereoisomer or as a mixture of two or morestereoisomers. Enantiomers are stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is aracemate or racemic mixture. Diastereomers (or diastereoisomers) arestereoisomers that are not enantiomers, i.e. they are not related asmirror images. If a compound contains a double bond, the substituentsmay be in the E or the Z configuration. Substituents on bivalent cyclic(partially) saturated radicals may have either the cis- ortrans-configuration; for example if a compound contains a disubstitutedcycloalkyl group, the substituents may be in the cis or transconfiguration. Therefore, the invention includes enantiomers,diastereomers, racemates, E isomers, Z isomers, cis isomers, transisomers and mixtures thereof, whenever chemically possible.

The meaning of all those terms, i.e. enantiomers, diastereomers,racemates, E isomers, Z isomers, cis isomers, trans isomers and mixturesthereof are known to the skilled person.

The absolute configuration is specified according to theCahn-Ingold-Prelog system. The configuration at an asymmetric atom isspecified by either R or S. Resolved stereoisomers whose absoluteconfiguration is not known can be designated by (+) or (−) depending onthe direction in which they rotate plane polarized light. For instance,resolved enantiomers whose absolute configuration is not known can bedesignated by (+) or (−) depending on the direction in which they rotateplane polarized light. When a specific stereoisomer is identified, thismeans that said stereoisomer is substantially free, i.e. associated withless than 50%, preferably less than 20%, more preferably less than 10%,even more preferably less than 5%, in particular less than 2% and mostpreferably less than 1%, of the other stereoisomers. Thus, when acompound of formula (I) is for instance specified as (R), this meansthat the compound is substantially free of the (S) isomer; when acompound of formula (I) is for instance specified as E, this means thatthe compound is substantially free of the Z isomer; when a compound offormula (I) is for instance specified as cis, this means that thecompound is substantially free of the trans isomer.

Some of the compounds according to formula (I) may also exist in theirtautomeric form. Such forms in so far as they may exist, although notexplicitly indicated in the above formula (I) are intended to beincluded within the scope of the present invention.

It follows that a single compound may exist in both stereoisomeric andtautomeric form.

For the avoidance of doubt, compounds of formula (I) may contain thestated atoms in any of their natural or non-natural isotopic forms. Inthis respect, embodiments of the invention that may be mentioned includethose in which (a) the compound of formula (I) is not isotopicallyenriched or labelled with respect to any atoms of the compound; and (b)the compound of formula (I) is isotopically enriched or labelled withrespect to one or more atoms of the compound. Compounds of formula (I)that are isotopically enriched or labelled (with respect to one or moreatoms of the compound) with one or more stable isotopes include, forexample, compounds of formula (I) that are isotopically enriched orlabelled with one or more atoms such as deuterium, ¹³C, ¹⁴C, ¹⁴N, ¹⁵O orthe like.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms that the compounds of formula (I) are able toform. These pharmaceutically acceptable acid addition salts canconveniently be obtained by treating the base form with such appropriateacid. Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric,nitric, phosphoric and the like acids; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e.ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic,fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds of formula (I) may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecularassociation comprising a compound of the invention and one or morepharmaceutically acceptable solvent molecules, e.g. water or ethanol.The term ‘hydrate’ is used when said solvent is water. Interestingcompounds of formula (I) are those compounds of formula (I) wherein oneor more of the following restrictions apply:

-   a) R¹ is hydrogen; or-   b) R¹ is C₁₋₄alkyl, mono- or di(C₁₋₄alkyl)amino, or Heterocyclyl¹;    or-   c) R¹ is Heterocyclyl¹; or-   d) R² is hydrogen; or-   e) R² is C₁₋₄alkyl; or-   f) R³ is C₃₋₆cycloalkyl; or-   g) R³ is C₁₋₄alkyl, mono- or di(C₁₋₄alkyl)amino; or-   h) R³ is Heterocyclyl²; or-   i) R⁴ is hydrogen; or-   j) Heterocyclyl¹ is piperazinyl optionally substituted with one    substituent selected from C₁₋₄alkyl, hydroxy, halo,    polyhaloC₁₋₄alkyl, C₁₋₄alkyloxycarbonyl, amino,    C₁₋₄alkylaminocarbonyl, or C₁₋₄alkylsulfonyl; or-   k) Heterocyclyl¹ is morpholinyl optionally substituted with one    substituent selected from C₁₋₄alkyl, hydroxy, halo,    polyhaloC₁₋₄alkyl, C₁₋₄alkyloxycarbonyl, amino,    C₁₋₄alkylaminocarbonyl, or C₁₋₄alkylsulfonyl; or-   l) Het is quinazolinyl optionally substituted with one, two or three    substitutents each independently selected from halo, C₁₋₄alkyl,    C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxy, amino, mono- or    di(C₁₋₄alkyl)amino, hydroxycarbonyl, C₁₋₄alkyloxycarbonyl,    C₁₋₄alkylsulfonylamino, aminocarbonyl, trifluoromethyl,    C₁₋₄alkyloxycarbonylamino, di(C₁₋₄alkyloxycarbonyl)amino,    C₁₋₄alkylsulfonylaminocarbonyl, C₁₋₄alkylaminocarbonyl,    C₁₋₄alkyloxyC₁₋₆alkyloxycarbonylamino,    di(C₁₋₄alkyl)aminosulfonylaminocarbonyl,    C₃₋₆cycloalkylsulfonylaminocarbonyl, HO—NH—(C═NH)—; oxazolyl or    triazolyl each optionally substituted with one or two C₁₋₄alkyl.

In a first embodiment the present invention concerns compounds offormula (I), including any stereochemically isomeric form thereof,wherein

-   R¹ is hydrogen, C₁₋₄alkyl, mono- or di(C₁₋₄alkyl)amino, or    Heterocyclyl¹;-   R² is hydrogen or C₁₋₄alkyl;-   R³ is C₃₋₆cycloalkyl or Heterocyclyl²;-   R⁴ is hydrogen;-   Heterocyclyl¹ is piperazinyl or morpholinyl; wherein each    Heterocyclyl¹ is optionally substituted with one substituent    selected from C₁₋₄alkyloxycarbonyl, C₁₋₄alkylaminocarbonyl, or    C₁₋₄alkylsulfonyl;-   Heterocyclyl² is azetidinyl, or pyrrolidinyl; wherein each    Heterocyclyl² is optionally substituted with one substituent    selected from hydroxy or amino;-   Het is selected from quinazolinyl, pyrido[2,3-d]pyrimidinyl,    thiazolo[5,4-d]-pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl,    oxazolo[5,4-d]pyrimidinyl, or thieno[2,3-d]pyrimidinyl; wherein each    Het is optionally substituted with one, two or three substitutents    each independently selected from halo, C₁₋₄alkyl, C₁₋₄alkyloxy,    C₁₋₄alkylthio, hydroxy, hydroxycarbonyl, C₁₋₄alkyloxycarbonyl,    C₁₋₄alkylsulfonylamino, aminocarbonyl, trifluoromethyl,    C₁₋₄alkyloxy-carbonylamino, di(C₁₋₄alkyloxycarbonyl)amino,    C₁₋₄alkylsulfonylamino-carbonyl, C₁₋₄alkylaminocarbonyl,    C₁₋₄alkyloxyC₁₋₆alkyloxycarbonylamino,    di(C₁₋₄alkyl)aminosulfonylaminocarbonyl,    C₃₋₆cycloalkylsulfonylamino-carbonyl, HO—NH—(C═NH)—; oxazolyl or    triazolyl each optionally substituted with one or two C₁₋₄alkyl;    or a pharmaceutically acceptable acid addition salt thereof.

A first group of compounds of formula (I) are those compounds of formula(I) wherein R¹ is Heterocyclyl¹, R² is hydrogen, and R³ isHeterocyclyl².

A second group of compounds of formula (I) are those compounds offormula (I) wherein R¹ is hydrogen, R² is C₁₋₄alkyl, and R³ isHeterocyclyl².

A third group of compounds of formula (I) are those compounds of formula(I) wherein R¹ is hydrogen, R² is hydrogen, and R³ is Heterocyclyl².

A fourth group of compounds of formula (I) are those compounds offormula (I) wherein R¹ is C₁₋₄alkyl, R² is hydrogen, and R³ isHeterocyclyl².

A 5^(th) group of compounds of formula (I) are those compounds offormula (I) wherein R¹ is hydrogen, R² is hydrogen, and R³ is C₁₋₄alkyl.

A 6^(th) group of compounds of formula (I) are those compounds offormula (I) wherein R¹ is hydrogen, R² is hydrogen, and R³ isC₃₋₆cycloalkyl.

A 7^(th) group of compounds of formula (I) are those compounds offormula (I) wherein Het is quinazolinyl.

Compounds of formula (I), or their pharmaceutically acceptable salts,can be prepared according to the reaction schemes discussed herein belowusing synthetic methods known in the art of organic chemistry, ormodifications and derivatisations that are familiar to those skilled inthe art. The starting materials used herein are commercially availableor may be prepared by routine methods known in the art such as thosemethods disclosed in standard reference books. Preferred methodsinclude, but are not limited to, those described below.

During any of the following synthetic sequences it may be necessaryand/or desirable to protect sensitive or reactive groups on any of themolecules concerned. This can be achieved by means of conventionalprotecting groups well known the skilled person.

Unless otherwise indicated, the substituents in the schemes are definedas above. Isolation and purification of the products is accomplished bystandard procedures, which are known to a chemist of ordinary skill.

General schemes 1-3 describe methods that were used to prepare compoundsof the invention. The general methods described in these schemes canalso be used to prepare additional compounds of the invention.

The starting material I is a protected (PG) piperidine bearing acarboxyl group on the carbon atom adjacent to the ring nitrogen thatpreferably has the (S) stereochemistry. This piperidine can also besubstituted with different groups. Protecting groups on the piperidinering nitrogen are preferably BOC or CBZ and can be introduced or removedduring the synthesis using methods described in; Green and Wutts,protecting groups in Organic Synthesis 3^(rd) Edition. In scheme 1 thecarboxylic acid group on the N-protected cyclic aminoheterocycle I isfirst activated with a leaving group. Typical leaving groups are alkylester (e.g. methyl or ethyl ester) and these are generated by treatmentof the carboxylic acid with the appropriate alcohol under non- orlow-aqueous acidic conditions or by treatment with methyl iodide in thepresence of a base like cesium carbonate or a like. Alternatively theacid can be activated as the Weinreb amide using standard peptidecoupling procedures e.g. EDCI/HOBT, HATU, DCC, etc. Once the acid isactivated as the ester or Weinreb amide II, the addition of anacetonitrile anion is performed. The anion generated from acetonitrileand a strong base e.g. lithium or sodium haxamethyldisilazide (LiHMDS)or alkyl lithium bases e.g. nBuLi, and when reacted with the ester orWeinreb amide generates the cyano ketone III. Reaction of the cyanoketone with hydrazine acetate salt then generates the aminopyrrazoleintermediate IV. This is a key intermediate in the formation of thebicyclic heterocycles VI with different side chains through differentcondensation reactions. Condensation of amino pyrrazole IV with themalonate V generates the bicyclic analog VI. Treatment of VI with neatPOCl₃ under elevated temperature (in some cases organic bases likediisopropylethyl amine or triethylamine can improve the reaction) thenaffords the dichloride VII. Under the POCl₃ conditions acidic labileprotecting groups e.g. BOC are typically removed but if this is partialfurther treatment with acid e.g. 4N HCl in dioxane can be used to removethe remaining BOC protected material. If other protecting groups areutilized then procedures described in Green and Wutts, Protecting groupsin Organic Synthesis 3^(rd) Edition can be used to remove the protectinggroup. Displacement of the chloride adjacent to the bridgehead nitrogenon VII can be effected with nucleophiles VIII, typically at roomtemperature to provide IX. A typical nucleophile VIII would be an aminethat can be reacted in the absence or presence of a base such astriethylamine. The second and less reactive chloride is then displacedtypically at elevated temperatures above 50° C. The result of thesenucleophilic amine displacements are compounds of structure XI (scheme1).

Compounds XIII may be synthesized according to embodiments disclosedherein from a compound having an amino group XI, and a heterocyclichalide compound XII. The reaction may be performed in the presence of abase and a Group 8-10 transition metal catalyst. One example of areaction between a heterocyclic halide compound and an amine to producean N-heterocyclic amine compound may be represented in scheme 2.Briefly, an heterocyclic halide XII compound is reacted with an aminecompound XI in the presence of a base and a Group 8-10 transition metal(M) complex including a chelating ligand (LL) to form an N-aryl aminecompound. The transition metal catalyst according to embodimentsdisclosed herein is a Group 8-10 transition metal complex. In certainembodiments, the Group 8-10 transition metal comprises at least one ofpalladium, platinum, and nickel. In some embodiments, the Group 8-10transition metal is palladium.

The heterocyclic compound used in the process of the present inventionmay be any heterocyclic compound of formula XII:

Het-X  formula XII

Preferred heterocyclic groups in compound of formula XII:

In formula XII, X may be any halide atom (F, Cl, Br, I), or anysulfur-containing leaving group (e.g., triflate, sulfonate, tosylate,and the like) known in the art. Chlorides are especially preferred inthe process of the present invention.

An alternative condensation of the aminopyrrazole IV using beta-ketoesters VIX (e.g. 2-methylacetoacetate) in the presence of acid (aceticacid) at elevated temperature leads to the pyrrazo-pyrimidinone scaffoldXV. Treatment of XV with neat POCl₃ under elevated temperature (in somecases hindered bases like diisopropylethyl amine can improve thereaction) then affords the dichloride XVI. Under the POCl₃ conditionsacidic labile protecting groups e.g. BOC are typically removed but ifthis is partial further treatment with acid e.g. 4N HCl in dioxane canbe used to remove the remaining BOC protected material. If otherprotecting groups are utilized then procedures described in Green andWutts, Protecting groups in Organic Synthesis 3^(rd) Edition can be usedto remove the protecting group. Displacement of the chloride adjacent tothe bridgehead nitrogen on XVI can be effected with nucleophiles VIII,typically at room temperature to provide compounds of type XVII. Atypical nucleophile would be an amine that can be reacted in the absenceor presence of a base such as triethylamine then allows the free amineXVII to be alkylated by a variety of heterocycles as described in scheme2 to produces the final compounds XVIII scheme 3.

A further alternative cyclisation of the amino pyrrazole IV involvestreatment with an acrylate e.g. XIX in the presence of base e.g. cesiumcarbonate, and heat to generate XX. Further treatment of XX to activatethat OH as a leaving group can include conversion to a chloride XXIusing POCl₃ and heat. Acidic protecting groups e.g. BOC can be removedunder the POCl₃ conditions, or if not, following procedures outlined inGreen and Wurtts, Protecting groups in Organic Synthesis 3^(rd) Edition,any protecting groups can be removed. The chloride can be displaced bynucleophiles X to generate compounds XXII. Finally the free NH compoundXXII is then alkylated as previously described in scheme 2 to givecompounds of type XXIII (scheme 4).

The compounds of formula (I) may further be prepared by convertingcompounds of formula (I) into each other according to art-known grouptransformation reactions.

The starting materials and some of the intermediates are known compoundsand are commercially available or may be prepared according toconventional reaction procedures generally known in the art.

The compounds of formula (I) as prepared in the hereinabove describedprocesses may be synthesized in the form of racemic mixtures ofenantiomers which can be separated from one another following art-knownresolution procedures. Those compounds of formula (I) that are obtainedin racemic form may be converted into the corresponding diastereomericsalt forms by reaction with a suitable chiral acid. Said diastereomericsalt forms are subsequently separated, for example, by selective orfractional crystallization and the enantiomers are liberated therefromby alkali. An alternative manner of separating the enantiomeric forms ofthe compounds of formula (I) involves liquid chromatography using achiral stationary phase. Said pure stereochemically isomeric forms mayalso be derived from the corresponding pure stereochemically isomericforms of the appropriate starting materials, provided that the reactionoccurs stereospecifically. Preferably if a specific stereoisomer isdesired, said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The compounds of formula (I) show antiviral properties. Viral infectionstreatable using the compounds and methods of the present inventioninclude those infections brought on by ortho- and paramyxoviruses and inparticular by human and bovine respiratory syncytial virus (RSV). Anumber of the compounds of this invention moreover are active againstmutated strains of RSV. Additionally, many of the compounds of thisinvention show a favorable pharmacokinetic profile and have attractiveproperties in terms of bioavailabilty, including an acceptablehalf-life, AUC and peak values and lacking unfavourable phenomena suchas insufficient quick onset and tissue retention.

The in vitro antiviral activity against RSV of the present compounds wastested in a test as described in the experimental part of thedescription, and may also be demonstrated in a virus yield reductionassay. The in vivo antiviral activity against RSV of the presentcompounds may be demonstrated in a test model using cotton rats asdescribed in Wyde et al. in Antiviral Research, 38, p. 31-42 (1998).

Additionally the present invention provides pharmaceutical compositionscomprising at least one pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of formula (I).

In order to prepare the pharmaceutical compositions of this invention,an effective amount of the particular compound, in base or acid additionsalt form, as the active ingredient is combined in intimate admixturewith at least one pharmaceutically acceptable carrier, which carrier maytake a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirably in unitary dosage form suitable, preferably, for oraladministration, rectal administration, percutaneous administration orparenteral injection.

For example in preparing the compositions in oral dosage form, any ofthe usual liquid pharmaceutical carriers may be employed, such as forinstance water, glycols, oils, alcohols and the like in the case of oralliquid preparations such as suspensions, syrups, elixirs and solutions;or solid pharmaceutical carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their easyadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral injection compositions, thepharmaceutical carrier will mainly comprise sterile water, althoughother ingredients may be included in order to improve solubility of theactive ingredient. Injectable solutions may be prepared for instance byusing a pharmaceutical carrier comprising a saline solution, a glucosesolution or a mixture of both. Injectable suspensions may also beprepared by using appropriate liquid carriers, suspending agents and thelike. In compositions suitable for percutaneous administration, thepharmaceutical carrier may optionally comprise a penetration enhancingagent and/or a suitable wetting agent, optionally combined with minorproportions of suitable additives which do not cause a significantdeleterious effect to the skin. Said additives may be selected in orderto facilitate administration of the active ingredient to the skin and/orbe helpful for preparing the desired compositions. These topicalcompositions may be administered in various ways, e.g., as a transdermalpatch, a spot-on or an ointment. Addition salts of the compounds offormula (I), due to their increased water solubility over thecorresponding base form, are obviously more suitable in the preparationof aqueous compositions.

It is especially advantageous to formulate the pharmaceuticalcompositions of the invention in dosage unit form for ease ofadministration and uniformity of dosage. “Dosage unit form” as usedherein refers to physically discrete units suitable as unitary dosages,each unit containing a predetermined amount of active ingredientcalculated to produce the desired therapeutic effect in association withthe required pharmaceutical carrier. Examples of such dosage unit formsare tablets (including scored or coated tablets), capsules, pills,powder packets, wafers, injectable solutions or suspensions,teaspoonfuls, tablespoonfuls and the like, and segregated multiplesthereof.

For oral administration, the pharmaceutical compositions of the presentinvention may take the form of solid dose forms, for example, tablets(both swallowable and chewable forms), capsules or gelcaps, prepared byconventional means with pharmaceutically acceptable excipients andcarriers such as binding agents (e.g. pregelatinised maize starch,polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like),fillers (e.g. lactose, microcrystalline cellulose, calcium phosphate andthe like), lubricants (e.g. magnesium stearate, talc, silica and thelike), disintegrating agents (e.g. potato starch, sodium starchglycollate and the like), wetting agents (e.g. sodium laurylsulphate)and the like. Such tablets may also be coated by methods well known inthe art.

Liquid preparations for oral administration may take the form of e.g.solutions, syrups or suspensions, or they may be formulated as a dryproduct for admixture with water and/or another suitable liquid carrierbefore use. Such liquid preparations may be prepared by conventionalmeans, optionally with other pharmaceutically acceptable additives suchas suspending agents (e.g. sorbitol syrup, methylcellulose,hydroxypropylmethylcellulose or hydrogenated edible fats), emulsifyingagents (e.g. lecithin or acacia), non-aqueous carriers (e.g. almond oil,oily esters or ethyl alcohol), sweeteners, flavours, masking agents andpreservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).

Pharmaceutically acceptable sweeteners useful in the pharmaceuticalcompositions of the invention comprise preferably at least one intensesweetener such as aspartame, acesulfame potassium, sodium cyclamate,alitame, a dihydrochalcone sweetener, monellin, stevioside sucralose(4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose) or, preferably,saccharin, sodium or calcium saccharin, and optionally at least one bulksweetener such as sorbitol, mannitol, fructose, sucrose, maltose,isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey.Intense sweeteners are conveniently used in low concentrations. Forexample, in the case of sodium saccharin, the said concentration mayrange from about 0.04% to 0.1% (weight/volume) of the final formulation.The bulk sweetener can effectively be used in larger concentrationsranging from about 10% to about 35%, preferably from about 10% to 15%(weight/volume).

The pharmaceutically acceptable flavours which can mask the bittertasting ingredients in the low-dosage formulations are preferably fruitflavours such as cherry, raspberry, black currant or strawberry flavour.A combination of two flavours may yield very good results. In thehigh-dosage formulations, stronger pharmaceutically acceptable flavoursmay be required such as Caramel Chocolate, Mint Cool, Fantasy and thelike. Each flavour may be present in the final composition in aconcentration ranging from about 0.05% to 1% (weight/volume).Combinations of said strong flavours are advantageously used. Preferablya flavour is used that does not undergo any change or loss of tasteand/or color under the circumstances of the formulation.

The compounds of formula (I) may be formulated for parenteraladministration by injection, conveniently intravenous, intra-muscular orsubcutaneous injection, for example by bolus injection or continuousintravenous infusion. Formulations for injection may be presented inunit dosage form, e.g. in ampoules or multi-dose containers, includingan added preservative. They may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulating agents such as isotonizing, suspending, stabilizing and/ordispersing agents. Alternatively, the active ingredient may be presentin powder form for mixing with a suitable vehicle, e.g. sterilepyrogen-free water, before use.

The compounds of formula (I) may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter and/or otherglycerides.

In general it is contemplated that an antivirally effective daily amountwould be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administerthe required dose as two, three, four or more sub-doses at appropriateintervals throughout the day. Said sub-doses may be formulated as unitdosage forms, for example, containing 1 to 1000 mg, and in particular 5to 200 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention. Theeffective daily amount ranges mentioned hereinabove are therefore onlyguidelines.

Also, the combination of another antiviral agent and a compound offormula (I) can be used as a medicine. Thus, the present invention alsorelates to a product containing (a) a compound of formula (I), and (b)another antiviral compound, as a combined preparation for simultaneous,separate or sequential use in antiviral treatment. The different drugsmay be combined in a single preparation together with pharmaceuticallyacceptable carriers. For instance, the compounds of the presentinvention may be combined with interferon-beta or tumor necrosisfactor-alpha in order to treat or prevent RSV infections.

The invention will hereinafter be illlustrated with reference to thefollowing, non-limiting examples.

EXPERIMENTAL PART Abbreviations

(M+H)⁺ protonated molecular ionaq. aqueousBoc tert-butyloxycarbonylbr broadCH₃Cl chloroformCH₃CN acetonitrileCH₃OH methanolCH₃ONa sodium methanolated doubletDCM dichloromethane

DIEA N,N-diisopropylethylamine

DIPE diisopropyletherDMF dimethyl formamideDMSO dimethyl sulfoxideEt ethyleq. equivalentEtOAc ethyl acetateHOAc acetic acidLiHMDS lithium bis(trimethylsilyl)amidem/z: mass-to-charge ratioMe methylMeCN acetonitrileMeOH methanolEtOH ethanolMHz megahertzmin minute(s)N₂ nitrogenNa₂SO₄ sodium sulfateNMR nuclear magnetic resonance (spectroscopy)Pd(OAc)2 palladium (II) acetatePh phenylq quartetRT room temperatures singletsat saturatedt tripletTEA triethyl amineTFA trifluoroacetic acidTHF tetrahydrofuran

NMR

For a number of compounds, ¹H NMR spectra were recorded on a BrukerDPX-400 spectrometer operating at 400 MHz or on a Bruker DPX-360operating at 360 MHz using chloroform-d (deuterated chloroform, CDCl₃)or DMSO-d₆ (deuterated DMSO, dimethyl-d6 sulfoxide) as solvent. Chemicalshifts (δ) are reported in parts per million (ppm) relative totetramethylsilane (TMS), which was used as internal standard.

Optical Rotation:

The optical rotation was measured using a Perkin Elmer 341 polarimeter.[c]D₂₀ indicates the optical rotation measured with light at thewavelength of the D-line of sodium (589 nm) at a temperature of 20° C.The cell pathlength is 1 dm. Behind the actual value the concentrationand solvent of the solution which was used to measure the opticalrotation are mentioned.

Experimental Part A. Chemical of Intermediates and Compounds of Formula(I) Synthesis of4-(5-(azetidin-1-yl)-2-(1-(6-chloroquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP1

Step 1: Synthesis of (S)-1-tert-butyl 2-methylpiperidine-1,2-dicarboxylate 2

Potassium carbonate (108.50 g, 785.09 mmol) was added to a solution of(S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid 1 (90 g, 392.55mmol) in DMF (900 ml). Iodomethane (83.58 g, 588.82 mmol) was added tothe mixture. The mixture was stirred at room temperature overnight.Ethyl acetate was added to the reaction mixture. The resulting mixturewas washed with water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated under vacuum to give intermediate 2(90 g, yield: 85%).

m/z=244 (M+H)⁺.

Step 2: synthesis of tert-butyl2-(2-cyanoacetyl)piperidine-1-carboxylate3

To a solution of CH₃CN (1.30 ml, 24.66 mmol) in dry THF (40 ml) wasadded dropwise LiHMDS (22.61 ml, 22.61 mmol) at −78° C. The solution wasstirred for 20 minutes at −78° C. A solution of 2 (5 g, 22.55 mmol) indry THF (10 ml) was added dropwise to the mixture. The resulting mixturewas stirred for 2 hours. Then the mixture was cooled to −78° C. and asolution of HOAc (5 ml, 76.67 mmol) in THF (50 ml) was added dropwise tothe mixture. The solution was warmed to room temperature. The solventwas removed under vacuum. The residue was dissolved in ethyl acetate andwashed with brine, dried Na₂SO₄, filtered and concentrated under vacuumto give the crude intermediate 3 (4 g, yield: 69%).

m/z=253 (M+H)⁺.

Step 3: tert-butyl2-(5-amino-1H-pyrazol-3-yl)piperidine-1-carboxylate 4

Hydrazine hydrate (100 ml) and ethanol (500 ml) were added tointermediate 3 (80 g, 317.70 mmol). The mixture was stirred at roomtemperature overnight. The solvent was removed under vacuum. The residuewas dissolved in ethyl acetate, washed with brine.

The organic layer was dried over Na₂SO₄, filtered and concentrated undervacuum to give intermediate 4 (80 g, yield: 76%).

m/z=267 (M+H)⁺.

Step 4: synthesis of tert-butyl2-(7-hydroxy-5-oxo-4,5-dihydropyrazolo[1,5-a]-pyrimidin-2-yl)piperidine-1-carboxylate5

Intermediate 4 (70 g, 262.82 mmol) was dissolved in methanol (700 ml),then Dimethyl malonate (85.19 g, 394.23 mmol) was added to the solution,followed by the addition of a solution of CH₃ONa in CH₃OH (25%, 85.19 g,394.23 mmol). The reaction mixture was heated to reflux overnight. Thesolvent was removed under vacuum. Water was added to the residue, the pHwas adjusted to 6-7 by addition of acetic acid, the mixture wasextracted with ethyl acetate, the organic layer was washed with brine,dried over Na₂SO₄, filtered and concentrated under vacuum to giveintermediate 5 (85 g, yield: 63%) which was used for the next reactiondirectly.

m/z=335 (M+H)⁺.

Step 5: synthesis of5,7-dichloro-2-(piperidin-2-yl)pyrazolo[1,5-a]pyrimidine 6

Intermediate 5 (25 g, 74.77 mmol)) was added to neat POCl₃ (100 ml). Thereaction mixture was heated to 100° C. for 3 hours. The solvent wasevaporated to yield intermediate 6 (15 g, yield: 63%) which was used forthe next reaction directly.

m/z=272 (M+H)⁺.

Step 6: synthesis of4-(5-chloro-2-(piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)-morpholine7

Intermediate 6 (35 g, 129.08 mmol) was added to CH₃CN (100 ml) and H₂O(100 ml). To the above mixture was added NaHCO₃ (21.69 g, 258.16 mmol)and morpholine (11.25 g, 129.08 mmol). The reaction mixture was stirredat room temperature for 1 hour, solvents were then evaporated,dichloromethane was added, the mixture was filtered and the filtrate wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: dichloromethane:ethyl acetate from 1:0 to 0:1) toyield intermediate 7 (25 g, yield: 51%).

m/z=322 (M+H)⁺.

Step 7: synthesis of4-(5-(azetidin-1-yl)-2-(piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine8

Azetidine hydrochloride (29.07 g, 310.75 mmol) and TEA (62.89 g, 621.49mmol) were added to a solution of intermediate 7 (20 g, 62.15 mmol) inethanol (1000 ml). The resulting mixture was heated to 80° C. for 2hours. The solvent was evaporated. The resulting crude material waspurified by column chromatography over silica gel (eluent:methanol/ethyl acetate 1/10). The collected fractions were concentratedunder vacuum. The residue was dissolved in CH₃CN (200 ml). K₂CO₃ (100 g,723.54 mmol) was added to the solution. The mixture was stirredovernight at room temperature. The resulting mixture was filtered andevaporated to remove the solvent in vacuum. The residue was lyophilized.Intermediate 8 was isolated (6 g, yield: 27%).

m/z=343 (M+H)⁺.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.52-1.66 (m, 4H) 1.90 (m, 1H) 1.97 (m,1H) 2.37-2.40 (m, 2H) 2.79 (m, 1H) 3.31 (m, 1H) 3.55-3.58 (m, 4H) 3.81(m, 1H) 3.93-3.95 (m, 4H) 4.09-4.13 (m, 4H) 5.09 (s, 1H) 6.04 (s, 1H).

Step 8: synthesis of 4,6-dichloroquinazoline 9

Synthesis of 6-chloroquinazolin-4-ol 9-b

2-Amino-5-chlorobenzoic acid 9-a (5 g, 29 mmol) was added to formamide(30 ml). The reaction mixture was heated to 100° C. for 3 hours. Thesolid was collected by filtration. The solid was washed several timeswith ethanol to yield intermediate 9-b (5 g, 86%). m/z=181 (M+H)⁺.

Synthesis of 4,6-dichloroquinazoline 9

Intermediate 9-b (3 g, 16.61 mmol) was dissolved in CHCl₃ (30 ml).Oxalyl chloride (2.8 g, 33.22 mmol) and DMF (0.1 ml) were added. Themixture was heated to 100° C. for 3 hours. Solvent was evaporated to getintermediate 9 (2.5 g, yield: 68%).

m/z=200 (M+H)⁺.

Step 9: synthesis of4-(5-(azetidin-1-yl)-2-(1-(6-chloroquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP1

Intermediate 8 TFA salt (400 mg, 0.87 mmol) was dissolved inmethoxyethanol (20 mL), intermediate 9 (235 mg, 1.18 mmol) anddiisopropyl ethylamine (0.6 mL, 3.5 mmol) were added. The resultingmixture was stirred at 50° C. for 24 hours. The mixture was poured in aniced watered solution and stirred for 15 minutes. The solid wassuccessively filtered off, washed with water, dissolved indichloromethane, dried over MgSO₄ and filtered. The resulting solutionwas concentrated and the solid was dried in the oven to yield ayellowish solid compound P1 (380 mg, 85%).

m/z=506 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.86 (m, 5H), 1.99-2.12 (m, 1H),2.25-2.37 (m, 3H), 3.47-3.58 (m, 6H), 3.63-3.75 (m, 5H), 3.96-4.07 (m,5H), 4.21 (d, J=13.4 Hz, 1H), 5.25 (s, 1H), 5.81-5.86 (m, 1H), 5.89 (s,1H), 7.72 (dd, J=9.0, 2.2 Hz, 1H), 7.78 (d, J=9.0 Hz, 1H), 8.07 (d,J=2.2 Hz, 1H), 8.57 (s, 1H)

Synthesis of(S)-4-(5-(azetidin-1-yl)-2-(1-(6-chloroquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP2 and(R)-4-(5-(azetidin-1-yl)-2-(1-(6-chloroquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP3

Step 1: synthesis of4-(5-chloro-2-(1-(6-chloroquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine10

To a solution of intermediate 7 (1 g, 3.11 mmol) and intermediate 9(0.62 g, 3.11 mmol) in DMF (20 ml) was added K₂CO₃ (2.15 g, 15.54 mmol).The resulting mixture was stirred overnight at room temperature. Waterwas added, the mixture was extracted with ethyl acetate, the organiclayer was washed with brine, dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by columnchromatography over silica gel (eluent: petroleum ether:ethyl acetatefrom 10:1 to 0:1) to yield intermediate 10 (450 mg, yield: 27%).

m/z=485 (M+H)⁺.

Step 2: synthesis of(S)-4-(5-(azetidin-1-yl)-2-(1-(6-chloroquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP2 and(R)-4-(5-(azetidin-1-yl)-2-(1-(6-chloroquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP3

Azetidine hydrochloride (0.39 g, 4.13 mmol) and TEA (0.84 g, 8.26 mmol)were added to a solution of intermediate 10 (0.4 g, 0.83 mmol) inethanol (50 ml). The solution was heated to 80° C. for 2 hours. Thesolvent was evaporated. The residue was purified by SFC. The desiredfractions were collected and evaporated. The residue was lyophilized toyield compound P2 (44.10 mg, yield: 10%) and compound P3 (43.30 mg,yield: 10%).

m/z=506 (M+H)⁺.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.79-1.83 (m, 4H) 2.01-2.06 (m, 1H)2.37-2.49 (m, 3H) 3.45-3.49 (m, 3H) 3.55-3.63 (m, 2H) 3.80-3.90 (m, 4H)4.15 (m, 4H) 4.25 (m, 1H) 5.10 (s, 1H) 5.90 (s, 1H) 6.10 (s, 1H) 7.61(dd, J1=9.2 Hz, J2=2.4 Hz, 1H) 7.80 (d, J=9.2 Hz, 2H) 8.03 (d, J=2.0 Hz,1H) 8.68 (s, 1H).

P2: [α]_(D) ²⁰=−280.83° (589 nm, c=0.24 w/v %, DMF, 20° C.)

P3: [α]_(D) ²⁰=+270° (589 nm, c=0.24 w/v %, DMF, 20° C.)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP4

Step 1: synthesis of4-(5-chloro-2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine11 Synthesis of 6-methylquinazolin-4-ol 12-b

2-Amino-5-methylbenzoic acid 12-a (5 g, 33.08 mmol) was added toformamide (30 ml). The reaction mixture was heated to 100° C. for 6hours. The solid was collected by filtration and washed several timeswith ethanol to give intermediate 12-b (4.5 g, 76%).

m/z=161 (M+H)⁺.

Synthesis of 4-chloro-6-methylquinazoline 12

Intermediate 12-b (2.1 g, 13.11 mmol) was dissolved in CHCl₃ (30 ml).Oxalyl chloride (1.97 g, 23.26 mmol) and DMF (0.1 ml) were added. Themixture was heated to 100° C. for 3 hours. The solvent was evaporated toget intermediate 12 (1.5 g, 58%).

m/z=179 (M+H)⁺.

To a solution of intermediate 7 (0.5 g, 1.55 mmol) and intermediate 12(0.28 g, 1.55 mmol) in CH₃CN (10 ml) was added K₂CO₃ (1.07 g, 7.77mmol). The resulting mixture was stirred for 72 hours at 50° C. Thesolvent was evaporated and the residue was dissolved in CH₂Cl₂. Theresulting mixture was filtered and filtrate was evaporated. The residuewas purified by column chromatography over silica gel (eluent: petroleumether:ethyl acetate from 0:1 to 1:1) to yield intermediate 11 (350 mg,yield: 44%).

m/z=464 (M+H)⁺.

Step 2: synthesis of4-(5-chloro-2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP4

Azetidine hydrochloride (0.30 g, 3.24 mmol) and TEA (0.66 g, 6.47 mmol)were added to a solution of intermediate 11 (0.3 g, 0.65 mmol) inethanol (10 ml). The solution was heated to 80° C. for 2 hours. Thesolvent was evaporated. The residue was purified by HPLC. The desiredfraction was collected and neutralized to pH=8-9 with NaHCO₃ solutionand extracted with EtOAc. The organic layer was washed with brine, driedover Na₂SO₄ and filtered. The filtrate was concentrated under vacuum.The residue was lyophilized to yield compound P4 (111.00 mg, 35%).

m/z=485 (M+H)⁺.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.67-1.79 (m, 4H) 2.17 (m, 1H) 2.42 (m,6H) 3.43-3.45 (m, 3H) 3.60-3.61 (m, 2H) 3.81 (m, 4H) 4.11 (m, 4H) 4.23(m, 1H) 5.09 (s, 1H) 5.89 (s, 1H) 6.15 (s, 1H) 7.52 (d, J=9.2 Hz, 1H)7.76-7.78 (m, 2H) 8.66 (s, 1H).

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(2-chloro-6-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP5

A mixture of intermediate 8 (500 mg, 1.460 mmol, 1 eq.), thecommercially available 2,4-dichloro-6-methylquinazoline 13 (622 mg,2.920 mmol, 2 eq.) and Et₃N (443 mg, 4.38 mmol, 3 eq.) in ethanol (20ml) was stirred at 80° C. for 16 hours. The mixture was cooled to roomtemperature. The precipitate was filtered and collected. The solid waswashed with cooled ethanol (2×3 ml) to yield compound P5 (540 mg, 69%)

m/z=520 (M+H)⁺.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.66-1.88 (m, 4H) 1.97-2.13 (m, 1H)2.32-2.54 (m, 6H) 3.38-3.52 (m, 3H) 3.55-3.68 (m, 2H) 3.86 (m, 4H) 4.13(t, J=7.53 Hz, 4H) 4.34 (d, J=12.80 Hz, 1H) 5.10 (s, 1H) 5.96 (br. s.,1H) 6.13 (s, 1H) 7.51 (dd, J1=8.53, J2=1.51 Hz, 1H) 7.69 (d, J=8.53 Hz,1H) 7.74 (s, 1H).

Synthesis ofN-(4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-6-methylquinazolin-2-yl)methanesulfonamideP6

Palladium acetate (8.6 mg, 0.038 mmol, 0.1 eq.) was added to a mixtureof compound P5 (200 mg, 0.385 mmol, 1 eq.), methanesulfonamide (73 mg,0.77 mmol, 2 eq.), Xantphos (22 mg, 0.038 mmol, 0.1 eq.) and Cs₂CO₃ (250mg, 0.77 mmol, 2 eq.) in Dioxane (6 ml). The resulting mixture wasstirred at 90° C. for 1.5 hours under microwave. The precipitate wasfiltered and washed with ethyl acetate to yield the title compound P6(98 mg, 42.34%).

m/z=578 (M+H)⁺.

¹HNMR (400 MHz, CDCl₃): δ ppm 1.89 (m, 4H) 1.90 (m, 1H) 2.31 (s, 3H)2.40 (m, 2H) 2.51 (m, 1H) 3.20 (s, 3H) 3.50 (m, 3H) 3.68 (m, 1H) 3.89(m, 4H) 4.13 (m, 4H) 4.62 (br, 1H) 5.13 (s, 1H) 6.12 (s, 1H) 7.41-7.43(d, J=8.4 Hz, 1H) 7.46-7.49 (d, J=8.8 Hz, 1H) 7.66 (s, 1H).

(R)—N-(4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-6-methylquinazolin-2-yl)methanesulfonamideP7 and(S)—N-(4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-6-methylquinazolin-2-yl)methanesulfonamideP8

A purification was performed via Prep SFC (Stationary phase: ChiralpakDiacel AS 20×250 mm, Mobile phase: CO2, EtOH with 0.2% iPrNH2) givingboth relative enantiomers:

m/z=578 (M+H)⁺.

¹HNMR (400 MHz, CDCl₃): δ ppm 1.89 (m, 4H) 1.90 (m, 1H) 2.31 (s, 3H)2.40 (m, 2H) 2.51 (m, 1H) 3.20 (s, 3H) 3.50 (m, 3H) 3.68 (m, 1H) 3.89(m, 4H) 4.13 (m, 4H) 4.62 (br, 1H) 5.13 (s, 1H) 6.12 (s, 1H) 7.41-7.43(d, J=8.4 Hz, 1H) 7.46-7.49 (d, J=8.8 Hz, 1H) 7.66 (s, 1H).

Synthesis ofN-(4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-5-methylquinazolin-2-yl)methanesulfonamideP9

Synthesis of 2,4-dichloro-5-methylquinazoline 14

Step 1: synthesis of 5-methylquinazoline-2,4(1H,3H)-dione 14-b

2-Amino-6-methylbenzoic acid 14-a (10 g, 66.15 mmol) and urea (39.73 g,661.54 mmol) were heated to 160° C. and stirred for 6 hours, thereaction mixture was cooled to 100° C. and 40 ml of H₂O was added. Theobtained suspension was left to stir for 10 min and cooled to roomtemperature. The precipitate was filtered off and was dissolved in anaqueous 0.2 M sodium hydroxide solution (100 ml). The solution washeated to 100° C. for 5 min, causing a white precipitate to form. Thereaction mixture was stirred at room temperature overnight, the solutionwas neutralized to pH=7 with concentrated HCl and the white solid wasfiltered off. The obtained solid was washed with water, triturated withhot ethyl acetate (100 ml), and cooled to room temperature. The filtratewas collected and dried under vacuum to yield intermediate 14-b (6.4 g,yield: 49%).

m/z=177 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.64 (s, 3H) 6.93 (d, J=7.48 Hz, 1H)7.01 (d, J=8.14 Hz, 1H) 7.44 (t, J=7.81 Hz, 1H) 10.99 (s, 1H) 11.03 (br.s., 1H)

Step 2: synthesis of 2,4-dichloro-5-methylquinazoline 14

A mixture of intermediate 14-b (1 g, 5.68 mmol), diethylaniline (2.267ml, 14.19 mmol) in POCl₃ (5 ml) was refluxed for 2 hours. The mixturewas cautiously poured over crushed ice. The mixture was neutralized topH=7 with saturated NaHCO₃. The resulting mixture was extracted withCH₂Cl₂ (2×15 ml). The combined organic layers were washed with brine,dried over Na₂SO₄ and filtered. The filtrate was concentrated undervacuum to yield intermediate 14 (950 mg, yield: 68%).

m/z=214 (M+H)⁺.

Step 3: synthesis of4-(5-(azetidin-1-yl)-2-(1-(2-chloro-6-methylquinazolin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine15

A mixture of intermediate 8 (500 mg, 1.46 mmol), intermediate 14 (933.13mg, 4.38 mmol) and triethyl amine (443.21 mg, 4.38 mmol) in EtOH (20 ml)was stirred at 80° C. for 16 hours. The mixture was cooled to roomtemperature. The precipitate was filtered and collected. The solid waswashed with cooled ethanol (2×5 ml) to yield the desired compound 15(400 mg, 48%).

m/z=520 (M+H)⁺.

Step 4: synthesis ofN-(4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-5-methylquinazolin-2-yl)methanesulfonamideP9

To a mixture of compound 15 (200 mg, 0.385 mmol), methanesulfonamide(73.24 mg, 0.77 mmol), xantphos (23.15 mg, 0.04 mmol) and Cs₂CO₃ (250.88mg, 0.77 mmol) in dioxane (6 ml) Pd(OAc)₂ (9 mg, 0.04 mmol) were added.The resulting mixture was stirred at 120° C. for 1.5 h under microwave.The mixture was filtered. The precipitate was treated with MeOH andfiltered. The combined filtrates were concentrated under vacuum. Theresidue was purified and the pH of the fractions containing product wasadjusted to 7-8 with saturated NaHCO₃. The organic solvent wasevaporated under vacuum. The aqueous concentrate was extracted withCH₂Cl₂ (30 ml). The organic layer was concentrated under vacuum to yieldcompound P9 (105 mg, yield: 45%).

m/z=578 (M+H)⁺.

¹H NMR (400 MHz, CDCl3) δ ppm 1.55-1.85 (m, 4H) 2.10-2.62 (m, 5H)2.69-2.85 (m, 5H) 3.35 (s, 3H) 3.59-3.86 (m, 8H) 4.07-4.17 (m, 4H) 5.21(s, 1H) 5.75 (s, 1H) 7.17-7.23 (m, 2H) 7.55-7.58 (m, 1H).

Synthesis ofN-(4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)quinazolin-2-yl)methanesulfonamideP10

Step 1: synthesis of4-(5-(azetidin-1-yl)-2-(1-(2-chloroquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine16

The mixture of 8 (250 mg, 0.73 mmol, 1 eq.), 2,4-dichloroquinazoline(290 mg, 1.46 mmol, 2 eq.) and triethylamine (221 mg, 2.19 mmol, 3 eq.)in ethanol was stirred at 90° C. for 4 hours. The reaction wasconcentrated. The residue was purified by flash chromatography (50%EtOAc in petroleum ether) to obtain 16 in 75% purity. Aftercrystallization from EtOAc and petroleum ether, the title intermediate16 was obtained as a white solid (160 mg, 43.42%)

m/z=506 (M+H)⁺.

¹HNMR (CDCl₃ 400 MHz) δ ppm 1.72-1.84 (m, 4H) 2.03 (m, 1H) 2.38-2.50 (m,3H) 3.47-3.52 (m, 3H) 3.61-3.68 (m, 2H) 3.84-3.93 (m, 4H) 4.12-4.15 (t,J=7.4 Hz, 4H) 4.41-4.45 (d, J=12.80 Hz, 1H) 5.11 (s, 1H) 5.96 (br.s, 1H)6.15 (s, 1H) 7.29-7.33 (m, 1H) 7.66-7.70 (m, 1H) 7.78-7.80 (d, J=8.5 Hz,1H) 7.98-8.00 (d, J=8.3 Hz, 1H).

Step 2: synthesis ofN-(4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)quinazolin-2-yl)methanesulfonamideP10

A mixture of intermediate 16 (60 mg, 119 umol, 1 eq.),methanesulfonamide (34 mg, 357 umol, 3 eq.),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (14 mg, 0.2 eq.),palladium(II) acetate (5.3 mg, 0.2 eq.) and Cesium carbonate (116 mg,357 umol, 3 eq.) in 1,4-dioxane (5 mL) was stirred at 110° C. for 18 hunder N₂. The reaction mixture was diluted with water and extracted withEtOAc (3×20 mL). The combined organic layers were concentrated. Theresidue was purified by HPLC, and the fractions were lyophilized. Thesolid was treated with SAX-SPE to obtain compound P10 as a yellow solid(24 mg, 34%)

m/z=564 (M+H)⁺.

¹HNMR (400 MHz, CD₃OD,): δ ppm 1.89 (br, 4H) 2.22 (m, 1H) 2.58 (m, 3H)3.08 (s, 3H) 3.59 (br, 1H) 3.89 (d, 4H) 3.91 (m, 4H) 4.38 (t, J=7.5 Hz,4H) 4.62 (br, 1H) 5.27 (s, 1H) 6.29 (s, 1H) 6.33 (br, 1H) 7.39 (t, J=7.3Hz, 1H) 7.49 (d, J=8.5 Hz, 1H) 7.79 (t, J=7.3 Hz, 1H) 8.01 (d, J=8 Hz,1H).

Synthesis of4-(2-(5-(azetidin-1-yl)-6-methylpyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-6-methylquinazolineP11

Step 1: synthesis of tert-butyl2-(6-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]-pyrimidin-2-yl)piperidine-1-carboxylate18

The intermediate 4 (5.00 g, 18.08 mmol) was dissolved in dry DMF (112ml), then Cs₂CO₃ (9.00 g, 27.62 mmol) and (E)-ethyl3-ethoxy-2-methylacrylate 17 (4.30 g, 27.18 mmol) were added and themixture was heated at 130° C. for 3 days. DMF was evaporated and thedark brown oil was poured into iced water. After warming to roomtemperature, the product was extracted with EtOAc (3 times). The organiclayers were dried over Na₂SO₄, filtered and evaporated and the resultingresidue was purified by column chromatography eluting with a gradientstarting from 0% to 10% MeOH and dichloromethane. After evaporation ofthe concerning fractions, we obtain intermediate 18 as a yellow solid(1100 mg, 18%).

¹H NMR (400 MHz, CDCl₃) δ ppm 1.35-1.71 (m, 13H) 1.73-1.88 (m, 1H) 2.09(d, J=1.10 Hz, 3H) 2.32 (d, J=13.64 Hz, 1H) 2.70-2.92 (m, 1H) 3.93-4.13(m, 1H) 5.35-5.54 (m, 1H) 5.71 (s, 1H) 7.99 (s, 1H) 10.56-10.76 (m, 1H)

m/z=333.20 (M+H)⁺

Step 2: synthesis of5-chloro-6-methyl-2-(piperidin-2-yl)pyrazolo[1,5-a]pyrimidine 19

POCl₃ (6.15 ml, 66.19 mmol) was added to intermediate 18 (1100 mg, 3.31mmol) at room temperature, then the mixture was heated at 100° C. for1.5 hours. The reaction mixture was cooled to room temperature and POCl₃was evaporated. The residue was co-evaporated 3 times with toluene toget brown foam intermediate 19 which was used as such in the next step.

m/z=250.96 (M+H)⁺

Step 3: synthesis of4-(6-methyl-2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-5-yl)morpholine20

The crude intermediate 19 (150 mg, 0.30 mmol) and4-chloro-6-methylquinazoline 12 (107 mg, 0.60 mmol) were dissolved in2-methoxyethanol (3.79 ml) and then di-isopropylethyl amine (619 μl,3.59 mmol) was added. The solution was heated at 100° C. overnight. Theheating was stopped and the mixture was cooled to room temperature. Tothe reaction mixture was added morpholine (1.035 ml, 11.97 mmol) and themixture was heated at 70° C. for 3 hours. Then it was evaporated todryness. The resulting residue was purified by column chromatographyeluting with 2.5% (MeOH/NH₃) and dichloromethane. The oil obtained wasrecrystallized in di-isopropyl ether. The formed off-white crystals werefiltered to get intermediate 20 (52 mg, 38%).

m/z=444.25 (M+H)⁺

MP=180.64° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.57-1.80 (m, 4H) 1.92-2.08 (m, 1H) 2.24(s, 3H) 2.34-2.46 (m, 4H) 3.20-3.28 (m, 4H) 3.45 (br. t, J=11.20, 11.20Hz, 1H) 3.67-3.83 (m, 4H) 4.21 (br. d, J=13.90 Hz, 1H) 5.85 (br. s., 1H)6.20 (s, 1H) 7.64 (br. d, J=8.40 Hz, 1H) 7.71 (d, J=8.58 Hz, 1H) 7.83(br. s, 1H) 8.56 (s, 1H) 8.71 (s, 1H)

Step 4: synthesis of4-(2-(5-(azetidin-1-yl)-6-methylpyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-6-methylquinazolineP11

A solution of intermediate 20 (145 mg, 0.37 mmol), azetidinehydrochloride (69 mg, 0.74 mmol) and di-isopropylethyl ether (191 μl,1.11 mmol) in EtOH (10 ml) was heated at 65° C. for 3.5 hours. Allsolvent was evaporated and the yellow wet solid was refluxed inacetonitril. The remaining insoluble solid was filtered off hot and thefiltrate was cooled to room temperature. The mixture was stirredovernight. The crystals were filtered off and washed with acetonitril.The product was again recrystallized in MeOH and acetonitril. The whitecrystals were filtered and washed with acetonitril to get the titleproduct P11 (72 mg, 47%).

m/z=414.12 (M+H)⁺

MP=205.49° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.58-1.79 (m, 4H) 1.88-2.03 (m, 1H) 2.15(d, J=0.88 Hz, 3H) 2.27 (quin, J=7.59 Hz, 2H) 2.32-2.40 (m, 1H) 2.42 (s,3H) 3.37-3.49 (m, 1H) 4.15-4.28 (m, 5H) 5.77-5.84 (m, 1H) 5.96 (s, 1H)7.63 (dd, J=8.58, 1.76 Hz, 1H) 7.71 (d, J=8.58 Hz, 1H) 7.82 (br. s, 1H)8.40-8.45 (m, 1H) 8.56 (s, 1H)

Synthesis of1-(6-methyl-2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo-[1,5-a]pyrimidin-5-yl)azetidin-3-olP12

Compound P12 was prepared in the same manner as compound P11 usingintermediate 20 and azetidin-3-ol as starting materials.

m/z=430.12 (M+H)⁺

MP=233.08° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.53-1.80 (m, 4H) 1.87-2.03 (m, 1H) 2.14(s, 3H) 2.31-2.40 (m, 1H) 2.42 (s, 3H) 3.38-3.50 (m, 1H) 3.93 (dd,J=9.13, 4.73 Hz, 2H) 4.16-4.28 (m, 1H) 4.32-4.44 (m, 2H) 4.46-4.59 (m,1H) 5.61-5.71 (m, 1H) 5.76-5.84 (m, 1H) 5.98 (s, 1H) 7.58-7.67 (m, 1H)7.67-7.75 (m, 1H) 7.83 (br. s, 1H) 8.45 (br. s, 1H) 8.56 (s, 1H)

Synthesis of1-(6-methyl-2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo-[1,5-a]pyrimidin-5-yl)azetidin-3-amineP13

Step 1: synthesis of tert-butyl1-(6-methyl-2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-ylcarbamate21

Intermediate 21 was prepared in the same manner as compound P11 usingintermediate 20 and tert-butylazetidin-3-ylcarbamate as startingmaterials.

m/z=529.25 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40 (s, 9H) 1.67-1.89 (m, 4H) 1.98-2.11(m, 1H) 2.15 (d, J=0.88 Hz, 3H) 2.41-2.46 (m, 4H) 3.60-3.74 (m, 1H)4.02-4.11 (m, 2H) 4.27-4.37 (m, 1H) 4.37-4.46 (m, 2H) 4.61-4.75 (m, 1H)6.12 (s, 1H) 6.22-6.35 (m, 1H) 7.10-7.30 (m, 1H) 7.80-7.88 (m, 2H) 7.97(br. s, 1H) 8.37 (s, 1H) 8.74 (s, 1H)

Step 2: synthesis of1-(6-methyl-2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-amineP13

A solution of intermediate 21 (215 mg, 0.39 mmol) and a 4M solution ofHCl in dioxane (6 ml, 24 mmol) were stirred at room temperature for 2hours. Dioxane was evaporated and the crude was purified by columnchromatography eluting with a gradient starting from 0.5% to 10%(MeOH/NH₃) and dichloromethane. After evaporation of the solvent weobtain the title compound P13 as a white solid (18 mg, 10%).

m/z=429.20 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.57-1.75 (m, 4H) 1.88-2.03 (m, 1H)2.11-2.20 (m, 3H) 2.31-2.40 (m, 1H) 2.42 (s, 3H) 3.37-3.49 (m, 1H)3.70-3.89 (m, 3H) 4.16-4.27 (m, 1H) 4.29-4.39 (m, 2H) 5.76-5.84 (m, 1H)5.96 (s, 1H) 7.63 (dd, J=8.58, 1.76 Hz, 1H) 7.71 (d, J=8.36 Hz, 1H) 7.82(br. s, 1H) 8.42-8.46 (m, 1H) 8.55 (s, 1H).

Synthesis of 2-methoxyethyl4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]-pyrimidin-2-yl)piperidin-1-yl)-6-morpholinoquinazolin-2-ylcarbamateP14

Synthesis of methyl (4-chloro-6-morpholinoquinazolin-2-yl)carbamate 22

Step 1: synthesis of ethyl 5-morpholino-2-nitrobenzoate 22-a

Ethyl 5-fluoro-2-nitrobenzoate (5 g, 23.46 mmol) was dissolved in DMF(150 ml) and then morpholine (6.13 g, 70.37 mmol) was added. Thereaction mixture was stirred 4 hours at room temperature. The solventwas removed under reduced pressure and the crude was re-dissolved indichloromethane, washed with 1M HCl-solution, dried over MgSO₄, filteredand evaporated to dryness to yield intermediate 22-a.

Step 2: synthesis of ethyl 2-amino-5-morpholinobenzoate 22-b

Ethyl 5-morpholino-2-nitrobenzoate 22-a (6.574 g, 23.46 mmol) wasdissolved in a mixture of EtOH (150 ml) and THF (250 ml), then Pd/C(10%) (2.496 g, 2.35 mmol) was added and the reaction mixture was setunder a hydrogen atmosphere for 2 hours. The reaction mixture wasfiltered over dicalite and the filtrate was evaporated to drynessyielding the wanted intermediate 22-b as a brown solid (6.24 g,quantitative).

Step 3: synthesis of methyl4-hydroxy-6-morpholinoquinazolin-2-ylcarbamate 22-c

Ethyl 2-amino-5-morpholinobenzoate 22-b (6.24 g, 24.93 mmol),1,3-bis(methoxy-carbonyl)-2-methyl-2-thiopseudourea (5.91 g, 28.67 mmol)and acetic acid (7.14 ml, 124.65 mmol) were dissolved in 100 ml MeOH andstirred overnight at 75° C. Extra acetic acid (1 ml, 17.47 mmol) wasadded and the reaction mixture was stirred at 75° C. for 7 days. The pHwas set to 5 with acetic acid. The volatiles were evaporated to dryness.Then the residue was re-dissolved in 15 ml MeOH and 100 ml water wasadded. The precipitate was filtered off, washed with diethylether toyield the title intermediate 22-c as a brown solid (5.28 g, 70%).

Step 4: synthesis of methyl4-chloro-6-morpholinoquinazolin-2-ylcarbamate 22

Methyl (4-hydroxy-6-morpholinoquinazolin-2-yl)carbamate 22-c (1.00 g,3.29 mmol) was suspended in dry acetonitril (12.38 ml), then POCl₃ (1.15ml, 12.4 mmol) was added at room temperature and the mixture wasrefluxed for 4.5 hours. After cooling to room temperature, the reactionmixture was evaporated to dryness. The residue was co-evaporated withtoluene. The crude was dissolved in DCM and it was washed with saturatedsodium hydrogencarbonate solution in water. The organic layer was driedover Na₂SO₄, filtered and evaporated. The residue was triturated indi-isopropylether. The solid was filtered off to get the titleintermediate 22 as a dark brown solid.

m/z=323.15 (M+H)⁺

Step 5: synthesis of 2-methoxyethyl4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo-[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-6-morpholinoquinazolin-2-ylcarbamateP14

A solution of intermediate 8 (80 mg, 0.23 mmol), methyl(4-chloro-6-morpholino-quinazolin-2-yl)carbamate 22 (152 mg, 0.23 mmol)and diisopropyl ethyl amine (117 μl, 0.68 mmol) in 2-methoxyethanol(1.79 ml) was heated at 100° C. overnight. The solvents were evaporatedand the residue was purified by column chromatography eluting with agradient starting from 0.5% to 10% MeOH in DCM. After evaporation of thesolvent we obtain an oil that was triturated in di-isopropyl ether andthe suspension was sonicated for 5 minutes. The solid was filtered andwashed with some di-isopropyl ether to get the title compound P14 as abrown powder (38 mg, 24%).

m/z=673.34 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.58-1.80 (m, 4H) 1.93-2.06 (m, 1H)2.24-2.40 (m, 3H) 2.95-3.11 (m, 4H) 3.28 (s, 3H) 3.30-3.34 (m, 1H)3.42-3.59 (m, 6H) 3.64-3.75 (m, 8H) 4.01 (t, J=7.37 Hz, 4H) 4.14-4.22(m, 2H) 4.22-4.32 (m, 1H) 5.33 (s, 1H) 5.70-5.81 (m, 1H) 6.00 (s, 1H)7.17 (d, J=2.20 Hz, 1H) 7.51 (d, J=9.24 Hz, 1H) 7.56 (dd, J=9.68, 2.64Hz, 1H) 9.83 (br. s., 1H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP15

Synthesis of 4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine 23

2-Methyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one 23-a (10.54 g, 70.6 mmol)was dissolved in Toluene (20 mL) under inert atmosphere. DIPEA (24 mL,141 mmol, 2 eq.) and POCl₃ (19.5 mL, 212 mmol, 3 eq.) were addeddropwise at 70° C. and the mixture was then heated to 106° C. After 16hours, the solution was concentrated in vacuo, extracted with ethylacetate and washed with saturated NaHCO₃ solution. The combined organiclayers were dried over Na₂SO₄, and concentrated in vacuo to yield a greyoil which was suspended in water/heptanes to afford a white solidintermediate 23 (5.9 g, 50%).

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP15

To a solution of intermediate 8 (100 mg, 0.28 mmol) in isopropanol (3mL) was added intermediate 23 (47 mg, 0.28 mmol, 1 eq.) and Et₃N (0.118mL, 0.84 mmol, 3 eq.) in a sealed pressure tube. The solution was heatedto 140° C. and stirred during 16 hours. After cooling to roomtemperature, the solution was concentrated in vacuum and purified byPrep HPLC to yield the title compound P15 (36 mg, 27%).

m/z=474 (M+H)⁺

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.52-1.58 (m, 1H) 1.58-1.69 (m, 2H) 1.73(d, J=11.74 Hz, 1H) 1.91 (br. s., 1H) 2.24-2.32 (m, 2H) 2.32-2.38 (m,1H) 2.36 (s, 3H) 3.27 (t, J=12.03 Hz, 1H) 3.47 (br. s., 4H) 3.58-3.68(m, 4H) 3.97 (t, J=7.34 Hz, 4H) 4.61 (d, J=11.74 Hz, 1H) 5.23 (s, 1H)5.71 (s, 1H) 6.21 (br. s., 1H) 6.42 (br. s., 1H) 6.98 (br. s., 1H) 11.17(br. s., 1H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(2-ethoxypyrido[2,3-d]pyrimidin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP16

Step 1: synthesis of4-(5-(azetidin-1-yl)-2-(1-(2-chloropyrido[2,3-d]pyrimidin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine25

Intermediate 8 (200 mg, 0.584 mmol) was dissolved in ethanol (10 mL),then 2,4-dichloropyrido[2,3-d]pyrimidine 24 (117 mg, 0.58 mmol) andtriethylamine (177 mg, 1.75 mmol) were added. The resulting mixture wasstirred at 90° C. for 12 hours. The solvent was evaporated. This crudeproduct was purified by column chromatography over silica gel (eluent:methanol/ethyl acetate 1/10). The resulting residue was lyophilized toyield a white solid (78.3 mg, 27%).

Step 2: synthesis of4-(5-(azetidin-1-yl)-2-(1-(2-ethoxypyrido[2,3-d]pyrimidin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP16

To a solution of intermediate 25 (67 mg, 0.13 mmol) in EtOH (10 mL) wasadded 100 μL HCl.iPrOH (6N) and the solution was heated to 40° C. during16 hours. The resulting solution was concentrated in vacuum and purifiedby column chromatography eluting with a gradient starting from 0% to 10%MeOH in DCM. After evaporation the title compound P16 (20 mg, 25%) wasobtained.

m/z=516 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, J=7.04 Hz, 3H) 1.71 (br. s.,4H) 1.92-2.11 (m, 1H) 2.23-2.39 (m, 3H) 3.40-3.58 (m, 5H) 3.61-3.74 (m,4H) 4.01 (t, J=7.37 Hz, 4H) 4.20 (br. d, J=13.90 Hz, 1H) 4.40 (q, J=7.00Hz, 2H) 5.28 (s, 1H) 5.79-5.88 (m, 1H) 5.91 (s, 1H) 7.19 (dd, J=8.58,4.40 Hz, 1H) 8.38 (dd, J=8.14, 1.54 Hz, 1H) 8.76-8.82 (m, 1H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP17

Synthesis of 4-chloro-5-methylquinazoline 26

Step 1: synthesis of 5-methylquinazolin-4-ol 26-b

2-Amino-6-methylbenzoic acid 26-a (4 g, 26 mmol) was dissolved in 10 mLformamide and the solution was heated to 120° C. After 4 hours water wasadded and the solid filtered off. The solid was further washed withwater and dried into the oven yielding intermediate 26-b (3.25 g, 77%).

m/z=160 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.77 (s, 3H) 7.25 (d, J=7.48 Hz, 1H)7.46 (d, J=7.70 Hz, 1H) 7.62 (t, J=7.90 Hz, 1H) 7.98 (s, 1H) 11.89 (br.s, 1H)

Step 2: synthesis of 4-chloro-5-methylquinazoline 26

Into a solution of intermediate 26-b (100 mg, 0.62 mmol) in acetonitrile(2 mL) was added DIPEA (0.23 mL, 1.88 mmol, 3 eq.). The resultingsolution was heated to 70° C. and stirred for 10 minutes. POCl₃ was thenadded to the solution dropwise. After 16 hours, the solution wasconcentrated in vacuo to yield intermediate 26.

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP17

To a solution of intermediate 8 (230 mg, 0.67 mmol) in CH₃CN (10 mL) ina sealed tube was added DIPEA (2.3 mL, 13.4 mmol, 20 eq.) and4-chloro-5-methylquinazoline 26 (120 mg, 0.67 mmol, 1 eq.). The solutionwas heated at 120° C. and stirred during 16 hours. After cooling to roomtemperature, the solution was concentrated in vacuum and the crudepurified by Prep HPLC to yield compound P17 (28 mg, 9%).

m/z=485 (M+H)⁺

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.54-1.86 (m, 4H) 2.08-2.13 (m, 2H)2.28-2.33 (m, 2H) 2.86 (s, 3H) 3.28-3.31 (m, 2H) 3.39-3.44 (m, 2H)3.49-3.54 (m, 2H) 3.62-3.69 (m, 4H) 4.00 (t, J=7.41 Hz, 4H) 5.31 (s, 1H)5.75 (t, J=4.40 Hz, 1H) 5.97 (s, 1H) 7.37 (d, J=6.90 Hz, 1H) 7.60-7.63(m, 1H) 7.67-7.71 (m, 1H) 8.53 (s, 1H)

Synthesis of(R)-4-(5-(azetidin-1-yl)-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP18 and(S)-4-(5-(azetidin-1-yl)-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP19

A purification was performed via Prep SFC (Stationary phase: ChiralpakDiacel AS 20×250 mm, Mobile phase: CO2, EtOH with 0.2% iPrNH2) givingboth relative enantiomers:

P18: [α]_(D) ²⁰=+210.64° (589 nm, c=0.3855 w/v %, DMF, 20° C.)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(2-methylthiazolo[5,4-d]pyrimidin-7-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP20

Synthesis of 7-chloro-2-methylthiazolo[5,4-d]pyrimidine 27

Step 1: synthesis of 5-amino-6-chloropyrimidine-4-thiol 27-b

To a solution of sulfanylsodium hydrate (2.48 g, 33.54 mmol) in water (6mL) was added MeOH (50 mL) and 4,6-dichloropyrimidin-5-amine 27-a (5 g,30.49 mmol). The resulting mixture was stirred at reflux for one hourand at ambient temperature overnight. The mixture was evaporated and theresidue was dried in vacuo, to yield intermediate 27-b (3.63 g, 74%).

m/z=161 (M+H)⁺

Step 2: synthesis of 7-chloro-2-methylthiazolo[5,4-d]pyrimidine 27

A solution of 5-amino-6-chloro-pyrimidine-4-thiol 27-b (4.7 g, 29.1mmol) in triethylorthoacetate (150 mL) was stirred at 150° C. for onehour. The reaction mixture was allowed to cool to room temperature andwas then evaporated to dryness. The residue was triturated indiisopropylether with some acetonitrile. The precipitate was collectedby filtration and dried in vacuo to yield intermediate 27 (0.9 g, 4.85mmol)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(2-methylthiazolo[5,4-d]pyrimidin-7-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP20

A solution of intermediate 8 (378.9 mg, 1 mmol),7-chloro-2-methyl-thiazolo[5,4-d]-pyrimidine 27 (185.6 mg, 1 mmol),Hunig's base (0.7 mL, 4.22 mmol) and 2-methoxyethanol (10 mL) wasstirred at 100° C. overnight. The mixture was evaporated and the residuewas dissolved in dichloromethane and washed twice with water. Theorganic layer was dried over MgSO4, filtered and evaporated. The residuewas purified over silica with dichloromethane/methanol 100/0 to 95/5 asgradient. The corresponding fractions were evaporated. The residue wascrystallised in diisopropylether and 10% acetonitrile. The whitecrystals were collected by filtration and dried in vacuo to yieldcompound P20 (163 mg, 33%).

m/z=491.62 (M+H)⁺

mp: 229.8° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48-1.83 (m, 2H), 1.91-2.06 (m, 1H),2.29 (quin, J=7.5 Hz, 1H), 2.39 (d, J=13.7 Hz, 1H), 2.72 (s, 3H), 3.21(m, J=2.4 Hz, 1H), 3.42-3.54 (m, 4H), 3.56-3.70 (m, 4H), 3.98 (t, J=7.5Hz, 4H), 5.16-5.30 (m, 2H), 5.73 (s, 1H), 6.98 (br. s., 1H), 8.32 (s,1H)

Synthesis of4-(2-(5-(azetidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-6-methylquinazolineP21

Step 1: synthesis of7-methyl-2-(piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-5(4H)-one 29

The commercially available (Z)-ethyl 3-ethoxybut-2-enoate 28 (33 g,208.60 mmol) and Cs₂CO₃ (54 g, 165.74 mmol) were added to a solution ofintermediate 4 (30 g, 112.64 mmol) in DMF (180 ml). The mixture wasstirred at 110° C. for 12 hours. The precipitate was filtered off andwashed with ethyl acetate (100 ml). The filtrate was concentrated undervacuum. The residue was dissolved in ethyl acetate (300 ml) and washedwith brine (2×100 ml). The organic layer was dried (MgSO₄), filtered andthe filtrate was concentrated under vacuum. The residue was washed withisopropyl ether (200 ml) and then dried (vacuum, 45° C., 1 hour) toyield intermediate 29 (25 g, 65.37%).

m/z=233 (M+H)⁺

Step 2: synthesis of5-chloro-7-methyl-2-(piperidin-2-yl)pyrazolo[1,5-a]pyrimidine 30

A mixture of intermediate 29 (22.5 g, 67.69 mmol) in POCl₃ (377.5 g) wasstirred at 100° C. for 2 hours. The solvent was evaporated under vacuum.Acetonitrile (200 ml) was added. The mixture was neutralized with NH₃ (7M in methanol) to pH=8. The solvent was evaporated under vacuum. Theresidue was purified by column chromatography over silica gel (eluent:dichloromethane/methanol 10/1) to yield intermediate 30 (13.97 g,80.47%).

m/z=251 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.52-1.73 (m, 4H) 1.76-1.86 (m, 1H)1.99-2.02 (m, 1H) 2.70 (s, 3H) 2.83-2.88 (m, 1H) 3.15-3.18 (d, J=12.0Hz, 1H) 4.14-4.17 (dd, J1=10.8, J2=2.8 Hz, 1H) 6.81 (s, 1H) 7.14 (s, 1H)

Step 3: synthesis of4-(2-(5-chloro-7-methylpyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-6-methylquinazoline31

A solution of intermediate 30 (501.5 mg, 2 mmol) and4-chloro-6-methyl-quinazoline 12 (535.9 mg, 3 mmol) in methoxyethanol (5mL) was stirred at 120° C. overnight. The mixture was evaporated and theresidue was dissolved in dichloromethane, washed twice with water, driedover MgSO4, filtered and evaporated. The residue was purified oversilica with dichloromethane/methanol-NH3 98/2. The correspondingfractions were evaporated and the residue was crystallized indi-isopropylether with 10% acetonitrile. The greenish precipitate wasfiltered off and dried in vacuum to yield intermediate 31 (645 mg, 82%)

m/z=392.9 (M+H)⁺

mp: 154.2° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.62-1.81 (m, 2H), 2.45 (s, 3H), 2.69(s, 2H), 4.16 (br. s., 1H), 5.95 (br. s., 1H), 6.60 (s, 1H), 7.00 (s,1H), 7.63 (d, J=1.6 Hz, 1H), 7.66-7.79 (m, 1H), 7.86 (s, 1H), 8.55 (s,1H)

Synthesis of4-(2-(5-(azetidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-6-methylquinazolineP21

A solution of intermediate 31 (196.45 mg, 0.5 mmol), azetidinehydrochloride (93.56 mg, 1 mmol), Hunig's base (0.26 mL, 1.5 mmol) andethanol (5 mL) was stirred at 60° C., over weekend. The mixture wasevaporated and the residue was triturated in water and stirred for onehour. The precipitate was filtered off and recrystallized inacetonitrile. The white crystals were collected by filtration and driedin vacuo to yield compound P21 (175 mg, 84%)

m/z=413.5 (M+H)⁺

mp: 192.43° C.

¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.58-1.78 (m, 4H), 1.90-2.05 (m, 1H),2.25-2.39 (m, 3H), 2.43 (s, 3H), 2.54 (s, 3H), 4.03 (t, J=7.5 Hz, 4H),5.80 (br. s., 1H), 6.00 (s, 1H), 6.12 (d, J=1.1 Hz, 1H), 7.65 (d, J=1.8Hz, 1H), 7.68-7.74 (m, 1H), 7.89 (s, 1H), 8.57 (s, 1H)

Synthesis of4-(2-(5-(azetidin-1-yl)-6-methyl-7-(piperidin-1-yl)pyrazolo[1,5-a]-pyrimidin-2-yl)piperidin-1-yl)-6-methylquinazolineP22

Step 1: synthesis of tert-butyl2-(7-hydroxy-6-methyl-5-oxo-4,5-dihydropyrazolo-[1,5-a]pyrimidin-2-yl)piperidine-1-carboxylate33

Freshly prepared sodium methanolate (50 ml, 93.87 mmol) was added to asolution of intermediate 4 (5 g, 18.77 mmol) and diethyl2-methylmalonate 32 (3.93 g, 22.53 mmol) in methanol (50 ml). Thesolution was refluxed for 15 hours. The solvent was evaporated undervacuum. Water was added to the residue, the solution was adjusted topH=4-5 by addition of acetic acid. The mixture was extracted with ethylacetate (3×300 ml), the combined organic layers were washed with brine(2×100 ml), dried (Na₂SO₄), filtered and concentrated under vacuum togive the crude intermediate 33 (8.5 g, yield: 91%).

m/z=349 (M+H)⁺

Step 2:5,7-dichloro-6-methyl-2-(piperidin-2-yl)pyrazolo[1,5-a]pyrimidine 34

Phosphorus trichlorid (30 ml) was added to intermediate 33 (6.5 g, 18.66mmol) at 0° C. The mixture was stirred at 100° C. for 15 hours. Thesolvent was evaporated under vacuum. The residue was dissolved in CH₃CN(30 ml). The solution was adjusted to pH=7 by addition of ammoniamethanol solution. The solvent was evaporated under vacuum. The residuewas purified by column chromatography over silica gel (eluent:dichloromethane/methanol 20/1 (0.5% ammonia methanol solution)). Thedesired fractions were collected and the solvent was evaporated undervacuum. The residue was washed with ethyl acetate. The solid was driedunder vacuum to yield intermediate 34 (1.12 g, 21%).

m/z=286 (M+H)⁺

¹H NMR (400 MHz, CDCl₃) δ ppm 1.22-1.25 (m, 1H) 1.65-1.68 (m, 2H)2.04-2.08 (m, 1H) 2.24-2.28 (m, 2H) 2.53 (s, 3H) 3.08 (br. s., 1H) 3.57(br. s., 1H) 3.69-3.80 (m, 1H) 4.48 (br. s., 1H) 7.21 (s, 1H).

Step 3: synthesis of5-chloro-6-methyl-7-(piperidin-1-yl)-2-(piperidin-2-yl)pyrazolo-[1,5-a]pyrimidine35

A solution of intermediate 34 (1120 mg, 3.93 mmol), morpholine (377 mg,4.32 mmol), Hunig's base (1.35 mL, 7.85 mmol) in ethanol (25 mL) wasstirred at room temperature overnight. The mixture was evaporated andthe residue was crystallised in diisopropyl-ether with about 50%acetonitrile. The crystals were collected by filtration and dried invacuo to yield intermediate 35 (1060 mg, 80%)

m/z=335.8 (M+H)⁺

Step 4:4-(2-(5-chloro-6-methyl-7-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-6-methylquinazoline36

A solution of intermediate 35 (1060 mg, 3.16 mmol),4-chloro-6-methyl-quinazoline 12 (845.7 mg, 4.73 mmol), Hunig's base(1.1 mL, 6.32 mmol) and 2-methoxyethanol (20 mL) was stirred at 100° C.overnight. The mixture was evaporated and the residue was taken up inwater and extracted with dichloromethane 3 times. The combined organiclayer was successively dried over MgSO4, filtered and evaporated. Theresidue was purified over a silicagel chromatography withdichloromethane/methanol 98/2 as eluent. The corresponding fractionswere evaporated to yield intermediate 36 (1400 mg, 92%)

Step 5: synthesis of4-(2-(5-(azetidin-1-yl)-6-methyl-7-(piperidin-1-yl)pyrazolo-[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-6-methylquinazolineP22

Compound P22 was prepared in the same manner as compound P21 usingintermediate 36 as starting material.

m/z=498.6 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.58-1.87 (m, 4H) 1.98-2.06 (m, 1H) 2.07(s, 3H) 2.24 (quin, J=7.57 Hz, 2H) 2.34-2.40 (m, 1H) 2.42-2.46 (m, 3H)3.34-3.40 (m, 4H) 3.49 (br ddd, J=13.62, 10.60, 3.63 Hz, 1H) 3.64-3.71(m, 4H) 4.10 (t, J=7.67 Hz, 4H) 4.19 (br d, J=14.13 Hz, 1H) 5.81-5.88(m, 1H) 5.92 (s, 1H) 7.59 (dd, J=8.48, 1.61 Hz, 1H) 7.65-7.73 (m, 1H)7.86 (s, 1H) 8.53 (s, 1H)

Synthesis of1-(6-methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo-[1,5-a]pyrimidin-5-yl)azetidin-3-olP23

P24: [α]_(D) ²⁰=+251.32° (589 nm, c=0.3975 w/v %, DMF, 20° C.)

P25: [α]_(D) ²⁰=−264.8° (589 nm, c=0.375 w/v %, DMF, 20° C.)

Step 1: synthesis of4-(2-(5-chloro-6-methylpyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-5-methylquinazoline37

Intermediate 19 (500 mg, 1.72 mmol) was dissolved in 2-methoxyethanol(30 mL). DIPEA (0.89 mL, 5.17 mmol, 3 eq.) and4-chloro-5-methylquinazoline 26 (324.26 mg, 1.72 mmol, 1 eq.) were addedto the solution and heated to 80° C. After 16 hours stirring, thesolution was concentrated in vacuo and purified via columnchromatography (DCM/(NH₃/MeOH) 7N): 9/1) to yield the desiredintermediate 37 (735 mg, 86%).

LCMS m/z=393 (M+H)⁺

Step 2: synthesis of1-(6-methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-olP23

Intermediate 37 (735 mg, 1.5 mmol) was dissolved in EtOH (50 mL).Azetidin-3-ol hydrochloride (327 mg, 3 mmol, 2 eq.) and DIPEA (0.77 mL,4.5 mmol, 3 eq.) were added and the solution was heated to reflux during16 hours. The solution was then cooled to room temperature, ice wasadded and the solution was stirred for 1 hour. The solid was filteredoff and dried into the oven to yield compound P23 (440 mg, 68%) LCMSm/z=430 (M+H)⁺

¹H NMR (400 MHz, 420 K, DMSO-d₆) δ ppm 1.41-1.70 (m, 3H) 1.76-1.89 (m,1H) 2.11 (d, J=1.21 Hz, 3H) 2.13-2.31 (m, 2H) 2.81 (s, 3H) 3.42-3.60 (m,2H) 3.90 (dd, J=9.28, 4.84 Hz, 2H) 4.34 (t, J=8.10 Hz, 2H) 4.46-4.55 (m,1H) 4.73-5.12 (m, 1H) 5.47-5.58 (m, 1H) 5.64 (br. s., 1H) 7.21-7.33 (m,1H) 7.46-7.63 (m, 2H) 8.10 (s, 1H) 8.45 (s, 1H)

(R)-1-(6-methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]-pyrimidin-5-yl)azetidin-3-olP24 and(S)-1-(6-methyl-2-(1-(5-methylquinazolin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-olP25

These two enantiomers were isolated by SFC separation using compound P23A purification was performed via Prep SFC (Stationary phase: ChiralpakDiacel AS 20×250 mm, Mobile phase: CO2, EtOH with 0.2% iPrNH2) givingboth relative enantiomers:

Synthesis of1-(6-methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo-[1,5-a]pyrimidin-5-yl)azetidin-3-amineP26

Step 1: synthesis oftert-butyl(1-(6-methyl-2-(piperidin-2-yl)pyrazolo[1,5-a]-pyrimidin-5-yl)azetidin-3-yl)carbamate38

A solution of intermediate 19 (1300 mg, 5.185 mmol),tert-butylazetidin-3-ylcarbamate (1786 mg, 10.37 mmol) and Hunig's base(2 ml, 11.606 mmol) in EtOH (30 ml) was heated at 70° C. for 3 hours.After cooling to room temperature, dicalite was added and the mixturewas evaporated to dryness. The crude was purified by columnchromatography. The column was eluted with a gradient starting with 100%DCM to 10% MeOH and 90% DCM. The fractions containing product wereevaporated and the residue was recrystallized in ACN. After filtrationwe get a white crystalline solid, this is a mixture of the desired titleintermediate 38 and starting reagent tert-butylazetidin-3-ylcarbamate(2204 mg), which was used as such in the next step.

m/z=387.26 (M+H)⁺

Step 2: synthesis oftert-butyl(1-(6-methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)carbamate39

The crude made in step 1, intermediate 38 (250 mg, 0.647 mmol),4-chloro-5-methyl-quinazoline 26 (182 mg, 0.97 mmol) and Hunig's base(368 μl, 2.135 mmol) were mixed in 2-methoxyethanol (4.36 ml) and heatedat 100° C. for 3 hours. The reaction mixture was evaporated and theresidue was purified by column chromatography by eluting with a gradientstarting with 100% DCM to 5% MeOH and 95% DCM. All fractions containingproduct were evaporated to get yellow foam which was only 52% pure (315mg). The crude was used as such in step 3.

m/z=529.28 (M+H)⁺

Step 3:1-(6-methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]-pyrimidin-5-yl)azetidin-3-amineP26

The crude made in step 2, intermediate 39 (157 mg, 0.297 mmol) wasdissolved in DCM (1.9 ml). Then TFA (227 μl, 2.97 mmol) was added andthe reaction mixture was stirred at room temperature for 16 hours. Themixture was basified by 7 M NH₃ in MeOH and all solvents wereevaporated. The residue was triturated in water and the formed solid wasfiltered off and purified by column chromatography. The column waseluted with a gradient starting from 100% DCM to 10% (MeOH/NH₃) and 90%DCM. All pure fractions were evaporated to get the title product P26 asa white solid (76 mg, 59%).

m/z=429.30 (M+H)⁺

MP=221.07° C.

¹H NMR at 150° C. (400 MHz, DMSO-d₆) δ ppm 8.46 (s, 1H), 8.10 (s, 1H),7.64-7.53 (m, 2H), 7.28 (d, J=5.9 Hz, 1H), 5.75-5.37 (m, 2H), 4.41-4.22(m, 2H), 3.87-3.71 (m, 3H), 3.60-3.37 (m, 2H), 2.81 (s, 3H), 2.31-2.12(m, 2H), 2.10 (s, 3H), 1.94-1.32 (m, 6H)

Synthesis of1-(2-(1-(2,5-dimethylquinazolin-4-yl)piperidin-2-yl)-6-methyl-pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-amineP27

Synthesis of 4-chloro-2,5-dimethylquinazoline 40

Step 1: synthesis of 2,5-dimethyl-4H-benzo[d][1,3]oxazin-4-one 40-b

A solution of 2-amino-6-methylbenzoic acid 40-a (20.0 g, 132 mmol) inacetic anhydride (100 ml) was stirred at 140° C. for 3 hours. Themixture was concentrated under vacuum to give the title intermediate40-b (20.0 g, 77.7%).

Step 2: synthesis of 2,5-dimethylquinazolin-4(3H)-one 40-c

A mixture of intermediate 40-b (20.0 g, 114 mmol) and ammonium hydroxide(50 ml) was refluxed overnight. The mixture was cooled to 25° C. Thesolid was collected by filtration and washed with water. The filter cakewas dried under vacuum at 40° C. for 1 hour to yield the titleintermediate 40-c (20 g, 90.5%).

Step 3: synthesis of 4-chloro-2, 5-dimethylquinazoline 40

Triethyl amine (5.05 g, 49.9 mmol) was added to a mixture ofintermediate 40-c (2.90 g, 16.7 mmol) in phosphorus oxychloride (108 g,709 mmol) at 0° C. The mixture was refluxed for 3 hours. The solvent wasevaporated under vacuum. The residue was dissolved in toluene (50 ml)and the solution was added to ice water (50 g). The organic layer wasseparated and washed successively with water (2×50 ml), 10% aqueousNaHCO₃ solution (2×50 ml), water (2×50 ml), brine (50 ml). The organiclayer was dried (MgSO₄), filtered and the filtrate was concentratedunder vacuum to yield intermediate 40 (1.91 g, 58.61%)

¹H NMR (400 MHz, CDCl₃) δ ppm 2.80 (s, 3H) 3.00 (s, 3H) 7.41 (d, J=7.28Hz, 1H) 7.68-7.76 (m, 1H) 7.78-7.85 (m, 1H).

Step 4: synthesis oftert-butyl(1-(2-(1-(2,5-dimethylquinazolin-4-yl)piperidin-2-yl)-6-methylpyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)carbamate41

The crude intermediate 38, (250 mg, 0.647 mmol), intermediate 40 (190mg, 0.97 mmol) and Hunig's base (368 μl, 2.135 mmol) were mixed in2-methoxyethanol (4.36 ml) and heated at 100° C. for 3 hours. Thereaction mixture was evaporated and the residue was purified by columnchromatography by eluting with a gradient starting with 100% DCM to 5%MeOH and 95% DCM. All fractions containing product were evaporated toget a yellow foam of intermediate 41 which was only 55% pure (427 mg).The crude was used as such in step 5.

m/z=543.36 (M+H)⁺

Step 5: synthesis of1-(2-(1-(2,5-dimethylquinazolin-4-yl)piperidin-2-yl)-6-methyl-pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-amineP27

The crude intermediate 41 (427 mg (only 55% pure), 0.433 mmol) wasdissolved in a 4 M solution of HCl in dioxane (21.64 ml, 86.551 mmol)and the reaction mixture was stirred at room temperature for 2 hours.The mixture was diluted with dichloromethane and then basified withsaturated Na₂CO₃ solution. The product was extracted withdichloromethane (3×15 mL). The organic layers were dried over Na₂SO₄,filtered and evaporated. The crude was purified by columnchromatography. The silica column was eluted with a gradient startingfrom 100% DCM to 4% (MeOH/NH₃) and 96% DCM. All pure fractions wereevaporated. The residue was triturated in DIPE to get the title productP27 as a white solid (11 mg, 6%).

m/z=443.6 (M+H)⁺

MP=176.85° C.

¹H NMR at 150° C. (400 MHz, DMSO-d₆) δ ppm 8.10 (s, 1H), 7.56-7.43 (m,2H), 7.19 (d, J=6.8 Hz, 1H), 5.74-5.44 (m, 2H), 4.39-4.25 (m, 2H),3.83-3.71 (m, 3H), 3.53-3.38 (m, 2H), 2.79 (s, 3H), 2.45 (s, 3H),2.26-2.13 (m, 2H), 2.11 (s, 3H), 1.94-1.38 (m, 6H)

Synthesis of dimethyl(4-{2-[5-(azetidin-1-yl)-7-(morpholin-4-yl)pyrazolo[1,5-a]-pyrimidin-2-yl]piperidin-1-yl}-5-methylquinazolin-2-yl)imidodicarbonateP28

Step 1: synthesis of4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-5-methylquinazolin-2-amine42

A suspension of intermediate 15 (1031 mg, 1.902 mmol) in a 7 M solutionof NH₃ in MeOH (25 ml, 175 mmol) was heated in a sealed metal reactor at120° C. for 4 days. After evaporation, the residue was purified by HPLCpurification. The purified product was dissolved in a mixture of DCM andDIPE, and the solution was evaporated again to get the titleintermediate 42 as a white solid (473 mg, 47%).

m/z=500.3 (M+H)⁺

MP=252.24° C.

¹H NMR at 150° C. (400 MHz, DMSO-d₆) δ ppm 7.36-7.27 (m, 1H), 7.16-7.10(m, 1H), 6.90-6.83 (m, 1H), 5.71-5.60 (m, 1H), 5.54-5.41 (m, 2H),5.31-5.22 (m, 1H), 5.17 (s, 1H), 3.98 (t, J=7.5 Hz, 4H), 3.78-3.28 (m,10H), 2.76 (s, 3H), 2.28 (quin, J=7.4 Hz, 2H), 2.21-2.07 (m, 2H),1.90-1.44 (m, 4H)

Step 2: synthesis of dimethyl(4-{2-[5-(azetidin-1-yl)-7-(morpholin-4-yl)pyrazolo-[1,5-a]pyrimidin-2-yl]piperidin-1-yl}-5-methylquinazolin-2-yl)imidodicarbonateP28

Intermediate 42 (100 mg, 0.188 mmol) was dissolved in DCM (2.21 ml).Then DIPEA (117 μl, 0.678 mmol) and methyl chloroformate (cas=79-22-1,29 μl, 0.376 mmol) were added. The reaction mixture was stirred at roomtemperature for 2 hours. DCM was evaporated and the residue wastriturated in water. The suspension was sonicated for 30 minutes andstirred at room temperature overnight. The solid was filtered and washedwith water and DIPE to obtain the title compound P28 as a white powder(40 mg, 31%).

m/z=616.6 (M+H)⁺

MP=136.62° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.79-7.66 (m, 1H), 7.65-7.55 (m, 1H),7.48-7.39 (m, 1H), 6.05-4.99 (m, 3H), 4.09-3.02 (m, 20H), 2.89-2.73 (m,3H), 2.38-1.94 (m, 4H), 1.87-1.40 (m, 4H)

Synthesis of methyl(4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]-pyrimidin-2-yl)piperidin-1-yl)-5-methylquinazolin-2-yl)carbamateP29

Compound P28 (200 mg, 0.279 mmol) was dissolved in MeOH (6.0 ml) and THF(6.0 ml). Then a solution of LiOH (17 mg, 0.722 mmol) in water (4.3 ml)was added.

The resulting mixture was stirred at room temperature for 3 hours. Thenit was neutralized with 1 M HCl solution and diluted with some water.The suspension was stirred at room temperature overnight. The whitesolid was collected by filtration and the desired product was dried invacuum oven overnight to yield a white solid P29 (71 mg, 43%).

¹H NMR at 80° C. (400 MHz, DMSO-d₆) δ ppm 9.70-9.32 (m, 1H), 7.53 (dd,J=7.3, 8.1 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.14 (d, J=7.0 Hz, 1H),6.25-4.79 (m, 3H), 3.99 (t, J=7.4 Hz, 4H), 3.80-3.67 (m, 5H), 3.65 (s,3H), 3.60-3.32 (m, 5H), 2.77 (s, 3H), 2.35-2.13 (m, 4H), 1.91-1.33 (m,4H)

m/z=558.3 (M+H)⁺

Synthesis of4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-N-hydroxy-5-methylquinazoline-2-carboximidamideP30

Step 1: synthesis of4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-5-methylquinazoline-2-carbonitrile43

A yellow solution of 15 (2000 mg, 3.689 mmol), zinc cyanide(cas=557-21-1, 521 mg, 4.433 mmol) and1,1′-bis(diphenylphosphino)ferrocene (cas=12150-46-8, 372 mg, 0.671mmol) in NMP (44.6 ml) was degassed with N₂ during 30 minutes. Thentris(dibenzylideneacetone)dipalladium(0) (cas=51364-51-3, 327 mg, 0.357mmol) was added and the reaction vessel was sealed and heated at 90° C.for 20 hours. The reaction mixture was quenched with water (176 ml) anda precipitation was formed immediately. This suspension was stirred atroom temperature overnight. The solid was filtered and washed with waterto get a dark brown solid. The wet brown solid was dissolved in DCM andthe remaining water was removed by separation and drying over Na₂SO₄.The residue was recrystallized in ACN and the mixture was stirredovernight. The black crystals were filtered, washed with ACN and MeOH toget purple/grey crystals. The solid was recrystallized again in ACN andstirred for 6 hours. Then the formed purple crystals intermediate 43 wasfiltered, washed with a little ACN and dried in the vacuum oven (1685mg, 81%).

m/z=510.3 (M+H)⁺

Step 2: synthesis of4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-N-hydroxy-5-methylquinazoline-2-carboximidamideP30

To a solution of hydroxylamine hydrochloride (3753 mg, 54 mmol) in water(12.5 ml) was added Na₂CO₃ (625 mg, 5.9 mmol) and the mixture wasstirred for 30 minutes. Then a suspension of intermediate 43 (1132 mg, 2mmol) in EtOH (50 ml) was added at room temperature. The resultingmixture was stirred for 16 hours. Iced water was added. After stirringfor 2 hours, the beige solid was filtered and washed with DIPE. Thecrude was suspended in a mixture of 95% DCM and 5% MeOH and theremaining precipitate was filtered off. The filtrate was purified bycolumn chromatography. The silica column was eluted by a gradientstarting with 100% DCM to 10% (MeOH/NH₃) and 90% DCM. After evaporationof the pure fractions we get the desired product P30 as a beige solid(38 mg, 3%).

m/z=543.6 (M+H)⁺

MP=205.46° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.82-9.46 (m, 1H), 7.71-7.56 (m, 2H),7.32 (dd, J=1.4, 6.3 Hz, 1H), 5.97-5.40 (m, 4H), 5.20 (s, 1H), 3.98 (t,J=7.4 Hz, 4H), 3.81-3.29 (m, 10H), 2.84 (s, 3H), 2.28 (quin, J=7.4 Hz,2H), 2.23-2.11 (m, 2H), 1.90-1.38 (m, 4H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(2-ethoxy-5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP31

A suspension of intermediate 15 (150 mg, 0.277 mmol) in EtOH (2.39 ml)was treated with NaOEt (21% in EtOH) (525 μl, 1.407 mmol). The samplewas flushed with N₂, sealed and heated at 80° C. for 48 hours. Thereaction mixture was evaporated to dryness and the residue was purifiedby column chromatography by eluting with a gradient starting from 100%DCM to 10% MeOH and 90% DCM. All fractions containing product wereevaporated to get white foam. The foam was recrystallized with DIPE and5% ACN and the mixture was stirred for 3 days. The white crystallinetitle compound P31 was obtained by filtration (46 mg, 29%).

m/z=529.3 (M+H)⁺

MP=186.90° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.52-7.42 (m, 1H), 7.35 (d, J=8.1 Hz,1H), 7.09 (d, J=7.0 Hz, 1H), 5.70-5.58 (m, 1H), 5.41-5.28 (m, 1H), 5.18(s, 1H), 4.39-4.27 (m, 2H), 4.05-3.90 (m, 4H), 3.74-3.57 (m, 4H),3.56-3.37 (m, 6H), 2.80 (s, 3H), 2.35-2.23 (m, 2H), 2.22-2.11 (m, 2H),1.94-1.40 (m, 4H), 1.27 (t, J=6.9 Hz, 3H)

Synthesis of(S)—N-(4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-6-chloroquinazolin-2-yl)methanesulfonamideP32

P33: [α]_(D) ²⁰=−209.83° (589 nm, c=0.3765 w/v %, DMF, 20° C.)

P34: [α]_(D) ²⁰=+192.15° (589 nm, c=0.242 w/v %, DMF, 20° C.)

Step 1: synthesis of4-(5-(azetidin-1-yl)-2-(1-(2,6-dichloroquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine45

Intermediate 8 (1341 mg, 2.92 mmol), 2,4,6-trichloroquinazoline 44(cas=20028-68-6, 768 mg, 2.83 mmol) and DIPEA (cas=7087-68-5, 1.24 ml,7.183 mmol) were mixed in 2-methoxyethanol (14.7 ml) and heated at 60°C. for 2 hours. The cooled reaction mixture was added slowly to icedwater and the mixture was warmed to room temperature. The formed brightyellow precipitate was successively filtered, washed with water and DIPEand dried in the vacuum oven. The product was purified by columnchromatography by eluting with a gradient starting with 100% DCM to 5%MeOH and 95% DCM. After evaporation of the fractions a yellow foam wasisolated as intermediate 45 (781 mg, 49%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.12 (d, J=2.2 Hz, 1H), 7.85 (dd, J=2.2,9.0 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 6.07 (s, 1H), 5.97-5.88 (m, 1H),5.35 (s, 1H), 4.34-4.20 (m, 1H), 4.02 (t, J=7.5 Hz, 4H), 3.77-3.60 (m,4H), 3.59-3.34 (m, 5H), 2.42-2.22 (m, 3H), 2.09-1.93 (m, 1H), 1.79-1.59(m, 4H)

m/z=539.3 (M+H)⁺

Step 2: synthesis ofN-(4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-6-chloroquinazolin-2-yl)methanesulfonamideP32

The intermediate 45 (750 mg, 1.39 mmol), methane sulfonamide (264 mg,2.781 mmol), cesium carbonate (cas=534-17-8, 1132 mg, 3.476 mmol),4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (cas=161265-03-8, 241mg, 0.417 mmol) and palladium(II)acetate (cas=3375-31-3, 94 mg, 0.417mmol) were mixed in dioxane (10 ml). The suspension was degassed with N₂for 10 minutes. The reaction vessel was sealed and then heated at 110°C. for 30 minutes in a g-wave oven. The reaction mixture was filteredand the filtrate was evaporated to dryness to be purified by columnchromatography by eluting with a gradient starting with 100% DCM to 10%(MeOH/NH₃) and 90% DCM. After evaporation of the concerning fractions weget the title product P32 as a brown solid (507 mg, 59%).

m/z=598.2 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.06 (br. s., 1H), 8.13-7.91 (m, 1H),7.76 (dd, J=2.2, 9.0 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 6.38-5.80 (m, 2H),5.37 (s, 1H), 4.56-4.30 (m, 1H), 4.03 (t, J=7.5 Hz, 4H), 3.79-3.64 (m,4H), 3.60-3.35 (m, 5H), 3.11-2.87 (m, 3H), 2.44-2.25 (m, 3H), 2.09-1.89(m, 1H), 1.82-1.60 (m, 4H)

Step 3: synthesis of(S)—N-(4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]-pyrimidin-2-yl)piperidin-1-yl)-6-chloroquinazolin-2-yl)methanesulfonamideP33 and(R)—N-(4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]-pyrimidin-2-yl)piperidin-1-yl)-6-chloroquinazolin-2-yl)methanesulfonamideP34

Compound P32 (400 mg, 0.669 mmol) was purified by SFC to obtain thetitle compound, pure enantiomer P33, as a yellowish solid (173 mg, 43%)and pure enantiomer P34, as a yellowish solid (187 mg, 46%).

P33, SFC: 100% pure, R_(t)=1.94 min

m/z=598.2 (M+H)⁺

P34, SFC: 98.65% Pure, 1.35% R_(t)=1.89 min and 98.65% R_(t)=2.74 min.

m/z=598.2 (M+H)⁺

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(5-chloroquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP35

To a solution of intermediate 8 (300 mg, 0.63 mmol) in 2-methoxyethanol(20 mL) was added 4,5-dichloroquinazoline 46 (CAS: 2148-55-2, 1.1 eq.,139 mg, 0.7 mmol) and DIPEA (3 eq., 0.33 mL, 1.9 mmol). The solution washeated to 80° C. for 16 hours. The solution was concentrated in vacuum,extracted with DCM and washed with water. The combined organics werecollected and dried with MgSO4, filtered off and concentrated in vacuum.The crude was purified by column chromatography eluting with a gradientstarting from 0% to 10% MeOH in DCM. After evaporation compound P35 (190mg, 57%) was obtained.

LCMS m/z=505 (M+H)⁺

¹H NMR (400 MHz, 420 K, DMSO-d₆) δ ppm 1.48-1.90 (m, 4H) 2.22-2.35 (m,4H) 3.43-3.56 (m, 5H) 3.64-3.76 (m, 4H) 3.84 (d, J=13.89 Hz, 1H)3.93-4.04 (m, 4H) 5.18 (s, 1H) 5.62 (s, 1H) 5.66 (br. s., 1H) 7.51 (dd,J=7.16, 1.61 Hz, 1H) 7.61-7.66 (m, 1H) 7.67-7.70 (m, 1H) 8.45 (s, 1H)

Synthesis of4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-N—(N,N-dimethylsulfamoyl)quinazoline-2-carboxamideP36

Step 1: synthesis of ethyl4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]-pyrimidin-2-yl)piperidin-1-yl)quinazoline-2-carboxylate48

To a solution of intermediate 8 (1.2 g, 3.4 mmol) in 2-methoxyethanol(40 mL) was added ethyl 4-chloroquinazoline-2-carboxylate 47 (0.97 g,4.06 mmol) and DIPEA (3 eq., 1.75 mL, 10 mmol). The solution was stirredat 80° C. for 48 hours. After cooling to room temperature the solutionwas concentrated in vacuum and purified by column chromatography elutingwith a gradient starting from 0% to 10% MeOH in DCM to give intermediate48 (998 mg, 75% pure, 40% yield) which was used as such into the nextstep.

LCMS m/z=543 (M+H)⁺

Step 2: synthesis of4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)quinazoline-2-carboxylicacid 49

To a solution of intermediate 48 (998 mg, 75% pure, 1.3 mmol) in 25 mlTHF/water (3/1), was added LiOH (3 eq., 93 mg, 3.9 mmol). The solutionwas stirred at room temperature during 16 hours. The solution was thenadjusted to pH=6 and the mixture was concentrated in vacuum givingintermediate 49 (828 mg, 76% pure, 94% yield), which was used as such inthe next step.

LCMS m/z=515 (M+H)⁺

Step 3: synthesis of4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-N—(N,N-dimethylsulfamoyl)quinazoline-2-carboxamideP36

To a solution intermediate 49 (300 mg, 0.37 mmol) was added CDI (120 mg,0.73 mmol) in 3 mL THF/DMF (1/1) solution. The solution was heated to50° C. and stirred for one hour. N,N-Dimethylsulfamide (136 mg, 1.1mmol) and DBU (0.165 mL, 1.1 mmol) was added to the solution and stirredfor an additional hour at 50° C. The solution was extracted with DCM andwashed with water. The combined organics were dried with MgSO₄ andconcentrated in vacuum. The crude was further purified by columnchromatography eluting with a gradient starting from 0% to 10% MeOH inDCM. After evaporation the crude was taken up in water and the solidfiltered off and dried into the oven to yield compound P36 (53 mg, 22%)as a white solid.

LCMS m/z=621 (M+H)⁺

¹H NMR (400 MHz, 360 K, DMSO-d₆) δ ppm 1.69-1.81 (m, 4H) 2.02-2.13 (m,1H) 2.26-2.35 (m, 3H) 2.35-2.42 (m, 1H) 2.90 (s, 6H) 3.49-3.57 (m, 5H)3.62-3.72 (m, 4H) 4.01 (t, J=7.48 Hz, 4H) 4.37 (d, J=13.42 Hz, 1H) 5.27(s, 1H) 5.94 (s, 1H) 6.05 (br. s, 1H) 7.57-7.61 (m, 1H) 7.83-7.88 (m,1H) 7.93 (dd, J=8.36, 1.10 Hz, 1H) 8.15 (d, J=8.58 Hz, 1H)

Synthesis of 1-(2-(1-(2,5-dimethylquinazolin-4-yl)piperidin-2-yl)-6-methyl-pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-olP37

Step 1: synthesis of4-(2-(5-chloro-6-methylpyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-2,5-dimethylquinazoline50

To a solution of intermediate 19 (200 mg, 0.58 mmol) in 2-methoxyethanol(40 mL) was added 4-chloro-2, 5-dimethyl-quinazoline 40 (1 eq., 114 mg,0.58 mmol, CAS nr. 147006-57-3) and DIPEA (3 eq., 0.3 mL, 1.7 mmol). Thesolution was heated to 80° C. for 16 hours. After cooling to roomtemperature the solution was concentrated in vacuum and purified bycolumn chromatography eluting with a gradient starting from 0% to 10%MeOH in DCM. After evaporation the crude was triturated with diethylether to afford intermediate 50 (140 mg, 90% pure, 53% yield). The solidwas used as such in the next step.

LCMS m/z=407 (M+H)⁺

Step 2: synthesis of1-(2-(1-(2,5-dimethylquinazolin-4-yl)piperidin-2-yl)-6-methyl-pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-olP37

Intermediate 50 (140 mg, 0.31 mmol) was dissolved in 5 mL EtOH at roomtemperature. Then azetidin-3-ol hydrochloride (68 mg, 0.62 mmol) andDIPEA (0.16 mL, 0.92 mmol) were added. The resulting solution wasrefluxed for 16 hours. The mixture was then concentrated in vacuum andtaken up in water/EtOH (3/1) the resulting solid was filtered off anddried into the oven to give compound P37 (65 mg, 48%).

LCMS m/z=444 (M+H)⁺

¹H NMR (400 MHz, 420 K, DMSO-d₆) δ ppm 1.41-1.70 (m, 3H) 1.76-1.89 (m,1H) 2.12 (d, J=0.81 Hz, 3H) 2.23-2.33 (m, 2H) 2.49 (s, 3H) 2.75 (s, 3H)3.53-3.64 (m, 2H) 3.94 (dd, J=9.69, 4.04 Hz, 2H) 4.36 (t, J=8.10 Hz, 2H)4.48-4.56 (m, 1H) 5.74 (br. s., 1H) 5.79 (br. s., 1H) 7.27 (d, J=7.27Hz, 1H) 7.43-7.54 (m, 1H) 7.55-7.63 (m, 1H) 8.12 (s, 1H)

Compound P37 (400 mg, 0.669 mmol) was purified by SFC to obtain thetitle compound, pure enantiomer P38 (44 mg):

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.47-1.77 (m, 4H) 1.86-2.00 (m, 1H) 2.13(d, J=0.66 Hz, 3H) 2.25-2.43 (m, 4H) 2.50 (s, 3H) 3.32-3.46 (m, 1H) 3.92(dd, J=9.79, 4.73 Hz, 2H) 4.20 (d, J=12.76 Hz, 1H) 4.28-4.42 (m, 2H)4.43-4.57 (m, 1H) 5.65 (d, J=6.16 Hz, 1H) 5.78 (br. s, 1H) 5.96 (s, 1H)7.56 (dd, J=8.80, 1.76 Hz, 1H) 7.60 (d, J=8.36 Hz, 1H) 7.76 (s, 1H) 8.45(s, 1H)

and pure enantiomer P39 (55 mg):

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.45-1.77 (m, 4H) 1.89-2.03 (m, 1H) 2.15(s, 3H) 2.28-2.43 (m, 4H) 2.51 (br. s., 3H) 3.35-3.47 (m, 1H) 3.94 (dd,J=9.79, 4.73 Hz, 2H) 4.23 (d, J=12.76 Hz, 1H) 4.38 (t, J=8.80 Hz, 2H)4.45-4.62 (m, 1H) 5.62 (br. s, 1H) 5.83 (br. s., 1H) 5.98 (s, 1H) 7.57(dd, J=8.58, 1.32 Hz, 1H) 7.62 (d, J=8.58 Hz, 1H) 7.78 (s, 1H) 8.46 (s,1H).

Synthesis ofN-(4-(2-(5-(3-hydroxyazetidin-1-yl)-6-methylpyrazolo[1,5-a]-pyrimidin-2-yl)piperidin-1-yl)-5-methylquinazolin-2-yl)methanesulfonamideP41

Step 1: synthesis of1-(6-methyl-2-(piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-azetidin-3-ol51

To a solution of the intermediate 19 (4.1 g, 11.9 mmol) in EtOH (50 mL)was added azetidin-3-ol hydrochloride (1.04 g, 14.3 mmol, 1.2 eq.) andDIPEA (10.2 mL, 60 mmol, 5 eq.) and the solution was refluxed overnight.After cooling to ambient temperature, the solution was concentrated invacuum. The crude was dissolved in DCM/MeOH (9/1) and the salts filteredoff. The filtrate was concentrated in vacuum and purified via columnchromatography (DCM/NH₃(MeOH 7N): 9/1) to obtain intermediate 51 (1.9 g,56%).

LCMS m/z=288 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.56-1.84 (m, 5H) 1.96-2.07 (m, 1H) 2.16(d, J=0.88 Hz, 3H) 2.82-2.96 (m, 1H) 3.16-3.23 (m, 1H) 3.95 (dd, J=9.57,4.95 Hz, 2H) 4.12 (dd, J=11.11, 2.97 Hz, 1H) 4.34-4.44 (m, 2H) 4.48-4.58(m, 1H) 6.16 (s, 1H) 8.40 (s, 1H).

Step 2: synthesis of1-(2-(1-(2-chloro-5-methylquinazolin-4-yl)piperidin-2-yl)-6-methylpyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-olP40

To a solution of intermediate 51 (500 mg, 1.74 mmol) in 2-methoxyethanol(30 mL) was added 2, 4-dichloro-5-methylquinazoline 14 (1.2 eq., 808 mg,2.08 mmol) and DIPEA (3 eq., 0.9 mL, 5.2 mmol). The solution was stirredat 50° C. during 2 hours and the mixture was concentrated in vacuum andextracted with DCM and washed with water. The combined organics weredried with MgSO₄ and concentrated in vacuum. The crude was furtherpurified on HPLC to give the title product P40 (130 mg, 16%).

LCMS m/z=464 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39-1.55 (m, 1H) 1.55-1.70 (m, 2H)1.73-1.89 (m, 1H) 2.05-2.20 (m, 4H) 2.23-2.32 (m, 1H) 3.43-3.70 (m, 2H)3.89-3.98 (m, 2H) 4.32-4.41 (m, 2H) 4.47-4.56 (m, 1H) 5.06-5.18 (m, 1H)5.59-5.68 (m, 1H) 5.68-5.79 (m, 1H) 7.25-7.33 (m, 1H) 7.44-7.52 (m, 1H)7.58-7.66 (m, 1H) 8.11-8.19 (m, 1H)

Step 3: synthesis ofN-(4-(2-(5-(3-hydroxyazetidin-1-yl)-6-methylpyrazolo[1,5-a]-pyrimidin-2-yl)piperidin-1-yl)-5-methylquinazolin-2-yl)methanesulfonamideP41

To a solution of compound P40 (130 mg, 0.28 mmol) in 1,4-dioxane (5 mL)was added methanesulfonamide (2 eq., 53 mg, 0.56 mmol), cesium carbonate(2.5 eq., 0.7 mmol, 228 mg),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.3 eq., 48.6 mg, 0.084mmol) and Pd(OAc)₂ (0.3 eq., 18.87 mg, 0.084 mmol) in a sealed tube. Themixture was heated to 120° C. during 5 minutes in a microwave. Thesolution was filtered over dicalite, washed with dichloromethane andconcentrated in vacuo. The crude was further purified by HPLC to givecompound P41 (42 mg, 30%) as a white powder.

LCMS m/z=523 (M+H)⁺

¹H NMR (400 MHz, 420 K, DMSO-d₆) δ ppm 1.46 (m, J=9.46 Hz, 1H) 1.62 (m,2H) 1.80 (m, 1H) 2.07-2.18 (m, 4H) 2.24-2.36 (m, 1H) 2.63 (s, 3H) 2.97(s, 3H) 3.57 (m, 1H) 3.68-3.80 (m, 1H) 3.90-3.98 (m, 2H) 4.33-4.41 (m,2H) 4.45-4.59 (m, 1H) 5.05 (br. s., 1H) 5.82 (br. s., 1H) 5.94 (br. s.,1H) 7.05 (d, J=7.04 Hz, 1H) 7.22 (d, J=8.14 Hz, 1H) 7.47 (t, J=7.05 Hz,1H) 8.16 (s, 1H) 9.88-11.04 (m, 1H).

Synthesis of1-(2-(1-(2,6-dimethylquinazolin-4-yl)piperidin-2-yl)-6-methyl-pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-olP42

Synthesis of 4-chloro-2,6-dimethylquinazoline 52

Step 1: synthesis of 2,6-dimethylquinazolin-4-ol 52-b

2-amino-5-methylbenzoic acid 52-a (8 g, 53 mmol) was dissolved in aceticanhydride (80 mL) and heated at 130° C. for 2 hours. The solution wasthen concentrated in vacuum to give the solid intermediate which wasfurther dissolved in a solution of EtOH (100 mL) and NH3.H2O (80 mL) andheated to 80° C. After 48 hours, the solution was cooled and the solidfiltered off and dried in the oven to give 2,6-dimethylquinazolin-4-ol52-b (6.3 g, 70%).

LCMS m/z=175 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.32 (s, 3H) 2.41 (s, 3H) 7.46 (d,J=8.36 Hz, 1H) 7.56 (dd, J=8.14, 1.98 Hz, 1H) 7.76-7.92 (m, 1H) 11.91(br. s, 1H)

Step 2: synthesis of 4-chloro-2,6-dimethylquinazoline 52

To a solution of 2,6-dimethylquinazolin-4-ol 52-b (500 mg, 2.87 mmol) inToluene (10 mL) was added DIPEA (0.989 mL, 5.74 mmol, 2 eq.) and POCl₃(0.4 mL, 4.3 mmol, 1.5 eq.). The solution was heated to 80° C. andstirred for 2 hours. The mixture was concentrated in vacuum and dilutedwith dichloromethane then washed with a saturated water solution ofNaHCO₃. The combined organics were dried with MgSO₄, concentrated invacuum and purified on column chromatography (Heptane/EtOAc: 1/1) togive intermediate 52 (300 mg, 90% purity, 48%).

LCMS m/z=193 (M+H)⁺

Step 3: synthesis of1-(2-(1-(2,6-dimethylquinazolin-4-yl)piperidin-2-yl)-6-methyl-pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-olP42

Intermediate 51 (240 mg, 0.83 mmol) was added to a solution of4-chloro-2,6-dimethylquinazoline 52 (1.7 eq., 300 mg, 1.4 mmol) andDIPEA (3 eq. 0.43 mL, 2.5 mmol) in 2-methoxyethanol (5 mL). The solutionwas heated at 140° C. and stirred for 16 hours. After cooling to ambienttemperature the mixture was extracted with DCM and washed with water.The combined organics were collected and dried with MgSO₄, filtered offand concentrated in vacuum. The crude was further purified by HPLC togive compound P42 (167 mg, 45%).

LCMS m/z=444 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.56-1.75 (m, 4H) 1.88-2.02 (m, 2H) 2.14(s, 3H) 2.34 (s, 1H) 2.39 (s, 3H) 3.94 (dd, J=9.46, 5.28 Hz, 2H) 4.20(d, J=12.76 Hz, 1H) 4.37 (t, J=8.10 Hz, 2H) 4.51 (br. s, 1H) 5.54-5.72(m, 1H) 5.81 (br. s, 1H) 5.96 (s, 1H) 7.53-7.63 (m, 2H) 7.77 (s, 1H)8.45 (s, 1H)

Synthesis of(S)-1-(2-(1-(2,6-dimethylquinazolin-4-yl)piperidin-2-yl)-6-methyl-pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-olP43 and(R)-1-(2-(1-(2,6-dimethyl-quinazolin-4-yl)piperidin-2-yl)-6-methylpyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-olP44

A further purification was performed via Prep SFC (stationary phase:chiralpak Diacel AS 20×250 mm, Mobile phase: CO₂, EtOH with 0.2% iPrNH₂)giving both relative entiomers:

P43:

LCMS m/z=444 (M+H)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.68 (s, 4H) 1.89-2.03 (m, 1H) 2.15 (s,3H) 2.28-2.43 (m, 4H) 2.51 (br. s., 3H) 3.35-3.47 (m, 1H) 3.94 (dd,J=9.79, 4.73 Hz, 2H) 4.23 (d, J=12.76 Hz, 1H) 4.38 (t, J=8.80 Hz, 2H)4.45-4.62 (m, 1H) 5.62 (br. s, 1H) 5.83 (br. s., 1H) 5.98 (s, 1H) 7.57(dd, J=8.58, 1.32 Hz, 1H) 7.62 (d, J=8.58 Hz, 1H) 7.78 (s, 1H) 8.46 (s,1H)

P44:

LCMS m/z=444 (M+H)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.47-1.77 (m, 4H) 1.86-2.00 (m, 1H) 2.13(d, J=0.66 Hz, 3H) 2.25-2.43 (m, 4H) 2.50 (s, 3H) 3.32-3.46 (m, 1H) 3.92(dd, J=9.79, 4.73 Hz, 2H) 4.20 (d, J=12.76 Hz, 1H) 4.28-4.42 (m, 2H)4.43-4.57 (m, 1H) 5.65 (d, J=6.16 Hz, 1H) 5.78 (br. s, 1H) 5.96 (s, 1H)7.56 (dd, J=8.80, 1.76 Hz, 1H) 7.60 (d, J=8.36 Hz, 1H) 7.76 (s, 1H) 8.45(s, 1H)

P43: [α]_(D) ²⁰=+295.23° (589 nm, c=0.377 w/v %, DMF, 20° C.)

P44: [α]_(D) ²⁰=−269.05° (589 nm, c=0.378 w/v %, DMF, 20° C.)

Synthesis of4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-5-methylquinazolin-2-olP45

A solution of intermediate 15 (100 mg, 0.193 mmol) in acetic acid (2 mL)was warmed to 70° C. for 3 hours. The reaction mixture was allowed tocool down to room temperature and water was added. The resulting mixturewas diluted with dichloromethane and washed with aqueous solution ofsodium bicarbonate. The organic layers were dried over MgSO4 and thesolvent was evaporated to yield product P45 (80 mg, 80%).

m/z=501.6 (M+H)⁺

MP=223.59° C.

¹H NMR at 100° C. (400 MHz, DMSO-d₆) δ ppm 10.31 (br. s., 1H), 7.35 (t,J=7.7 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 6.90 (d, J=7.5 Hz, 1H), 6.24-5.34(m, 2H), 5.24 (s, 1H), 4.10-3.43 (m, 14H), 2.65 (s, 3H), 2.37-2.06 (m,4H), 1.89-1.39 (m, 4H)

Synthesis of4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-5-methylquinazoline-2-carboxamideP46

To a solution of intermediate 43 (100 mg, 0.17 mmol) in DMF (5 mL) wasadded 10 mL NaOH (1M in H₂O) in a sealed tube. The solution was heatedto 130° C. for 10 minutes in a microwave. The solution was then adjustedto pH=6-7 with 1 molar aqueous solution of hydrochloric acid. Thesolution was further extracted with DCM, and the combined organics werewashed with a saturated NaHCO₃ solution and brine. The organic layer wasfurther dried with MgSO4 and concentrated in vacuum. The resultingmaterial was purified on HPLC to compound P46 (68 mg, 73%)

LCMS m/z=528 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14-1.87 (m, 4H) 1.98-2.41 (m, 4H) 2.84(s, 3H) 3.19-3.27 (m, 2H) 3.40-3.83 (m, 7H) 3.85-4.28 (m, 5H) 5.12-5.44(m, 2H) 5.87 (s, 1H) 7.38-7.50 (m, 1H) 7.55-7.81 (m, 3H) 7.89-8.03 (m,1H).

Synthesis of4-(5-cyclopropyl-6-methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP47

Step 1: synthesis of5-cyclopropyl-6-methyl-2-(piperidin-2-yl)pyrazolo[1,5-a]-pyrimidin-7-ol54

To a solution of intermediate 4 (16 g, 60 mmol) in acetic acid (100 mL)was added methyl 3-cyclopropyl-2-methyl-3-oxopropanoate 53 (30 g, 180mmol). The resulting mixture was stirred at 100° C. overnight.

The resulting mixture was concentrated under vacuum and the residue (46g, 98%) was used as such in the next step.

Step 2: synthesis of7-chloro-5-cyclopropyl-6-methyl-2-(piperidin-2-yl)pyrazolo-[1,5-a]pyrimidine55

The mixture of intermediate 54 (45 g, 79 mmol) and phosphoryltrichloride (220 g) was stirred at 110° C. for one hour. The solvent wasremoved and the residue was dissolved in ice watered solution andbasified by addition of sodium carbonate (19.8 g, 238 mmol). Thissolution was used as such in the next step.

Step 3: synthesis of4-(5-cyclopropyl-6-methyl-2-(piperidin-2-yl)pyrazolo[1,5-a]-pyrimidin-7-yl)morpholine56

To the solution of intermediate 55 acetonitrile (250 mL) and morpholine(20.7 g, 238 mmol) were added. The resulting mixture was refluxedovernight. The reaction mixture was allowed to cool down to roomtemperature and the solvent was removed under vacuum. The resultingwater solution was extracted with dichloromethane and the organic layerswere dried over Na2SO4 and concentrated. The residue was purified bycolumn chromatography using dichloromethane and methanol as eluent.Intermediate 56 (2 g, 7%) was isolated.

Step 4: synthesis of4-(5-cyclopropyl-6-methyl-2-(1-(5-methylquinazolin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP47

To a solution intermediate 56 (200 mg, 0.56 mmol) in 5 mL2-methoxyethanol was added 4-chloro-5-methyl-quinazoline 26 (1.2 eq.,126 mg, 0.67 mmol) and DIPEA (3 eq., 0.289 mL, 1.68 mmol). The solutionwas stirred at 80° C. for 48 hours. After cooling to room temperaturethe solution was concentrated in vacuo and purified on HPLC to give thetitle product P47 (110 mg, 41%).

LCMS m/z=484 (M+H)⁺

¹H NMR (400 MHz, 420 K, DMSO-d₆) δ ppm 0.90-1.11 (m, 4H) 1.50-1.61 (m,1H) 1.61-1.76 (m, 2H) 1.80-1.92 (m, 1H) 2.07-2.18 (m, 1H) 2.20-2.32 (m,2H) 2.35 (s, 3H) 2.84 (s, 3H) 3.28-3.40 (m, 4H) 3.47-3.65 (m, 2H)3.66-3.78 (m, 4H) 5.56-5.67 (m, 1H) 6.00 (br. s., 1H) 7.30 (d, J=6.46Hz, 1H) 7.55-7.66 (m, 2H) 8.46 (s, 1H)

Synthesis of (3S)-1-(6-methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-3-amineP48

Step 1: synthesis of tert-butyl2-(5-hydroxy-6-methylpyrazolo[1,5-a]pyrimidin-2-yl)-piperidine-1-carboxylate58

To a solution of intermediate 4 (14.43 g, 54.18 mmol) in DMF (270 ml),(E)-ethyl 3-ethoxy-2-methylacrylate 57 (9.00 g, 56.9 mmol) and Cs₂CO₃(26.48 g, 81.27 mmol) were added. The resulting mixture was stirred at130° C. for 12 hours. The solvent was evaporated under vacuum. Theresidue was successively dissolved in ethyl acetate (300 ml), washedwith saturated aqueous NH₄Cl solution, with brine and dried over Na₂SO₄.After filtration, the filtrate was concentrated under vacuum to 100 ml.After 16 hours, the precipitate was filtered off. The filter cake waswashed with ethyl acetate (2×30 ml) and dried (vacuum, 45° C., 1 hour)to give intermediate 58 (11.80 g, 65.52%).

Step 2: synthesis of5-chloro-6-methyl-2-(piperidin-2-yl)pyrazolo[1,5-a]pyrimidine 59

A mixture of intermediate 58 (11.80 g, 35.50 mmol) in phosphoryltrichloride (178 ml) was stirred at 80° C. for 1 hour. The solvent wasevaporated under vacuum. The residue was dissolved in acetonitrile (200ml). The mixture was neutralized with ammonia (7 M in methanol) topH=7-8. The precipitate was filtered off and the filtrate wasconcentrated. The residue was purified by flash column chromatographyover silica gel (eluent: dichloromethane/1% NH₃ in methanol 10/1). Thecollected fractions were concentrated to give intermediate 59 (3.715 g,40.44%).

Step 3: synthesis of tert-butyl((3S)-1-(6-methyl-2-(piperidin-2-yl)pyrazolo[1,5-a]-pyrimidin-5-yl)pyrrolidin-3-yl)carbamate61

The solution of intermediate 59 (3.58 g, 10.0 mmol, 70% purity),(S)-tert-butyl-pyrrolidin-3-ylcarbamate 60 (2.33 g, 12.5 mmol) and Et₃N(3.04 g, 30.0 mmol) in MeOH (50 ml) was stirred overnight at 70° C. Themixture was filtered and the filtrate was concentrated under vacuum. Theresidue was dissolved in CH₂Cl₂ and washed with brine. The separatedorganic layer was dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by silica column chromatography(eluent: CH₂Cl₂/MeOH 10:1). After concentration, the crude product wastriturated with CH₃CN. The solid was filtered and washed with CH₃CN togive the title intermediate 62 (768 mg, 12% yield)

¹H NMR (400 MHz, CDCl₃) δ ppm 1.45 (s, 9H) 1.62 (m, 1H) 1.90 (m, 3H)2.16 (m, 3H) 2.26 (s, 3H) 3.12 (m, 1H) 3.47 (m, 1H) 3.49 (s, 3H) 3.65(m, 1H) 3.72 (m, 1H) 3.84 (m, 1H) 4.26 (m, 1H) 4.37 (m, 1H) 4.90 (d, 1H,J=6.8 Hz) 6.39 (s, 1H) 7.99 (d, 1H, J=4.8 Hz).

Step 4: synthesis of tert-butyl((3S)-1-(6-methyl-2-(1-(5-methylquinazolin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-3-yl)carbamate62

The intermediate 61 (300 mg, 0.694 mmol), 4-chloro-5-methyl-quinazoline26 (170 mg, 0.902 mmol) and Hunig's base (395 μl, 2.291 mmol) were mixedin 2-methoxyethanol (4.7 ml) and heated at 80° C. for 2 hours. Aftercooling to room temperature, the reaction mixture was added slowly toiced water solution. The suspension was stirred at room temperature for2 hours. The formed precipitate was filtered off, washed with water andthen dried in the vacuum oven for 16 hours. The crude was purified bycolumn chromatography by eluting with a gradient starting with 100% DCMto 10% MeOH and 90% DCM. After evaporation of the pure fractions we getcrude of the title intermediate 62 (238 mg)

m/z=543.4 (M+H)⁺

Step 5: synthesis of(3S)-1-(6-methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-3-amineP48

Intermediate 62 (238 mg, 0.386 mmol), was dissolved in DCM (2.5 ml) andtrifluoroacetic acid (295 μl, 3.859 mmol) was added. The mixture wasstirred at room temperature for 16 hours. The reaction mixture was addeddrop wise to a cooled saturated solution of NaHCO₃. The product wasextracted with DCM (3 times). The organic layers were dried over Na₂SO₄,filtered and evaporated to dryness. The crude was purified by columnchromatography by eluting with a gradient starting with 100% DCM to 10%(MeOH/NH₃) and 90% DCM. After evaporation of the pure fractions a yellowfoam was isolated. The foam was triturated in diethyl ether to get thetitle product P48 as a white solid (152 mg, 85%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.46 (s, 1H), 8.15 (s, 1H), 7.68-7.51(m, 2H), 7.29 (d, J=6.4 Hz, 1H), 5.79-5.42 (m, 2H), 3.85-3.19 (m, 7H),2.80-2.75 (m, 3H), 2.28 (s, 3H), 2.25-1.28 (m, 8H)

m/z=443.3 (M+H)⁺

MP=124.92° C.

Synthesis of(3S)-1-(2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-3-amineP49

Step 1: synthesis of tert-butyl2-(5-hydroxypyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carboxylate 64

To a solution of intermediate 4 (5.00 g, 18.8 mmol) and1,3-dimethylpyrimidine-2,4(1H,3H)-dione 63 (2.90 g, 20.7 mmol) inethanol (50 mL) sodium ethoxide (22 ml, 66 mmol) was added. Theresulting solution was refluxed overnight. The solvent was evaporatedunder vacuum. Water was added to the residue and the pH was adjusted to4-5 with HCl (1 N). The mixture was extracted with ethyl acetate, theorganic layer was washed with brine, dried over Na₂SO4, filtered andconcentrated under vacuum to give the crude intermediate 64 (5 g, 75%).

Step 2: synthesis of5-chloro-2-(piperidin-2-yl)pyrazolo[1,5-a]pyrimidine 65

A mixture of intermediate 64 (5 g, 15.7 mmol) in POCl₃ (50 ml) wasstirred at 100° C. for 2 hours. The solvent was evaporated under vacuum.The residue was washed with tert-butylmethyl ether to yield intermediate65 (4.5 g, 19 mmol).

Step 3: synthesis oftert-butyl((3S)-1-(2-(piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-3-yl)carbamate66

A mixture of intermediate 65 (4.5 g, 19 mmol),(S)-tert-butylpyrrolidin-3-ylcarbamate 60 (7.0 g, 38 mmol) andtriethylamine (7.7 g, 76 mmol) in methanol (50 ml) was refluxedovernight. The mixture was filtered and the filtrate was concentratedunder vacuum. The residue was dissolved in CH₃CN and stirred with K₂CO₃(5.0 g, 38 mmol). The mixture was filtered and the filtrate wasconcentrated under vacuum. The residue was treated with H₂O and CH₂Cl₂.The separated organic layer was dried over Na₂SO₄, filtered andconcentrated under vacuum to give intermediate 66 (1.65 g, 22%).

¹H NMR (400 MHz, CDCl₃) δ ppm 1.45 (s, 9H) 1.51-1.72 (m, 1H) 1.83-1.93(m, 2H) 1.94-2.07 (m, 3H) 2.20-2.39 (m, 1H) 2.73-2.93 (m, 1H) 3.11-3.28(m, 1H) 3.35-3.49 (m, 1H) 3.53-3.74 (m, 1H) 3.75-3.95 (m, 1H) 4.24-4.45(m, 1H) 4.59-4.90 (m, 1H) 5.96-6.19 (m, 1H) 8.12-8.30 (m, 1H).

Step 4: synthesis oftert-butyl((3S)-1-(2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-3-yl)carbamate67

Intermediate 66 (250 mg, 0.624 mmol), 4-chloro-6-methylquinazoline 12(145 mg, 0.811 mmol) and DIPEA (355 μl, 2.058 mmol) were mixed in2-methoxyethanol (4.2 ml) and heated at 80° C. for 16 hours and at 90°C. for 1 hour. After cooling to room temperature, the reaction mixturewas added slowly to iced water. The suspension was stirred at roomtemperature overnight. The brown precipitate was filtered off, washedwith water and then dried in the vacuum oven for 16 hours. The crude ofthe title intermediate 67 (250 mg) was used as such in the next step.

m/z=529.4 (M+H)⁺

Step 5: synthesis of(3S)-1-(2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo-[1,5-a]pyrimidin-5-yl)pyrrolidin-3-amineP49

Intermediate 67 (250 mg, 0.473 mmol) was dissolved in DCM (3.0 ml) andTFA (362 μl, 4.729 mmol) was added. The reaction mixture was stirred atroom temperature for 16 hours. The reaction mixture was quenched withsaturated Na₂CO₃ solution and the product was extracted 3 times withDCM. The organic layers were evaporated and the product was purified bycolumn chromatography by eluting with a gradient starting with 100% DCMto 10% (MeOH/NH₃) and 90% DCM. After evaporation of the pure fractionswe get the desired product P49 as a yellow foam (122 mg, 56%).

m/z=429.3 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.63-8.53 (m, 2H), 7.82 (br. s, 1H),7.71 (d, J=8.6 Hz, 1H), 7.63 (dd, J=1.5, 8.6 Hz, 1H), 6.30 (d, J=7.7 Hz,1H), 5.91 (s, 1H), 5.84-5.77 (m, 1H), 4.29-4.17 (m, 1H), 3.72-2.99 (m,6H), 2.47-1.58 (m, 13H)

¹H NMR at 100° C. (400 MHz, DMSO-d₆) δ ppm 8.52 (s, 1H), 8.42 (dd,J=0.7, 7.7 Hz, 1H), 7.86-7.81 (m, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.58 (dd,J=1.8, 8.6 Hz, 1H), 6.24 (d, J=7.7 Hz, 1H), 5.86 (s, 1H), 5.84-5.79 (m,1H), 4.26-4.18 (m, 1H), 3.66-3.43 (m, 5H), 3.19-3.12 (m, 1H), 2.42 (s,3H), 2.40-2.30 (m, 1H), 2.14-1.92 (m, 3H), 1.86-1.59 (m, 6H)

Synthesis of(S)-1-(2-((R)-1-(6-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo-[1,5-a]pyrimidin-5-yl)pyrrolidin-3-amineP50

Product P49 (100 mg, 0.233 mmol) was purified by SFC to obtain the titlecompound, pure enantiomer, as an off white solid P50 (51 mg, 51%).

SFC: 100% pure at R_(t)=2.64 min

m/z=429.2 (M+H)⁺

P50: [α]_(D) ²⁰=−268.64° (589 nm, c=0.354 w/v %, DMF, 20° C.)

Synthesis of(S)-1-(2-((S)-1-(6-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo-[1,5-a]pyrimidin-5-yl)pyrrolidin-3-amineP51

Product P49 (100 mg, 0.233 mmol) was purified by SFC to obtain the titlecompound, pure enantiomer, as an off white solid P51 (17 mg, 17%).

SFC: 100% pure at R_(t)=3.68 min

m/z=429.3 (M+H)⁺

Synthesis oftert-butyl4-(5-(azetidin-1-yl)-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)piperazine-1-carboxylateP52

Step 1: synthesis oftert-butyl4-(5-chloro-2-(piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)piperazine-1-carboxylate69

A mixture of intermediate 6 (40.0 g, 125 mmol),tert-butylpiperazine-1-carboxylate 68 (25.7 g, 138 mmol) and NaHCO₃(26.30 g, 313.5 mmol) in CH₃CN (300 ml) and H₂O (300 ml) was stirred atroom temperature for 1 hours. The solvent was concentrated under vacuum.The concentrate was treated with CH₂Cl₂ (500 ml). The separated organiclayer was washed with brine (200 ml), filtered and concentrated undervacuum to afford the title intermediate 69 (40 g, yield: 68%).

Step 2: synthesis oftert-butyl4-(5-(azetidin-1-yl)-2-(piperidin-2-yl)pyrazolo[1,5-a]-pyrimidin-7-yl)piperazine-1-carboxylate70

A mixture of intermediate 69 (40 g, 95 mmol), azetidine hydrochloride(47.7 g, 510 mmol) and TEA (155.0 g, 1530 mmol) in ethanol (500 ml) wasrefluxed overnight. The mixture was filtered and the filtrate wasconcentrated under vacuum. The residue was treated with CH₂Cl₂ and H₂O.The separated organic layer was concentrated under vacuum. The residuewas purified by column chromatography over silica gel (eluent:dichloromethane/methanol (1% of TEA contained)=15/1). The productfractions were collected and the solvent was evaporated to afford thetitle intermediate 70 (17.96 g, yield 42.71%).

m/z=515 (M+H)⁺

¹H NMR (400 MHz, CDCl₃) δ ppm 1.49 (s, 9H) 1.52-1.68 (m, 4H) 1.91-2.05(m, 4H) 2.37-2.41 (m, 2H) 2.78-2.83 (m, 1H) 3.16-3.18 (m, 1H) 3.51-3.53(m, 4H) 3.67-3.68 (m, 4H) 3.79-3.82 (m, 1H) 4.09-4.4.13 (m, 4H) 5.10 (s,1H) 6.04 (s, 1H).

Step 3: synthesis oftert-butyl4-(5-(azetidin-1-yl)-2-(1-(5-methylquinazolin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)piperazine-1-carboxylateP52

The mixture of intermediate 70 (3 g, 5.83 mmol), intermediate 26 (1.56g, 8.75 mmol) was dissolved in 2-methoxyethanol (100 mL) thendiisopropylethyl amine (2 mL, 11.66 mmol) was added. The resultingmixture was stirred at 50° C. for three days. The mixture was allowed tocool down to room temperature and poured in iced watered solution. Theresulting mixture was stirred until all the ice is melt then theresulting solid was filtered off. The solid was successively washed withwater, dissolved in dichloromethane, dried over MgSO4 and concentrated.The resulting residue was purified by column chromatography usingdichloromethane and methanol to yield P52 (3.3 g, 87%) as a white lightyellow solid.

m/z=584 (M+H)⁺

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.39-1.49 (m, 9H), 1.53-1.91 (m, 4H),2.03-2.36 (m, 4H), 2.87 (s, 3H), 3.29-3.51 (m, 8H), 3.53-3.67 (m, 4H),3.90-4.04 (m, 2H), 5.40-5.51 (m, 1H), 5.64 (s, 1H), 6.25 (br. s., 1H),7.27-7.42 (m, 1H), 7.52-7.70 (m, 2H), 8.47 (s, 1H).

Synthesis of4-(2-(5-(azetidin-1-yl)-7-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-5-methylquinazolineP53

Compound P52 (3 g, 5.139 mmol) was dissolved in DCM (150 ml) and TFA (4ml, 51 mmol) was added. The reaction mixture was stirred at roomtemperature for 5 days. The reaction mixture was quenched with saturatedNa₂CO₃ solution and the product was extracted 3 times with DCM. Theorganic layers were evaporated and the product was purified by columnchromatography by eluting with a gradient starting with 100% DCM to 10%(MeOH/NH₃) and 90% DCM. After evaporation of the concerning fractions weget the desired product P53 as a yellow foam (2.3 g, 92%).

m/z=484 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.57 (br. s., 1H), 1.63-1.76 (m, 2H),1.80-1.95 (m, 1H), 2.15-2.27 (m, 2H), 2.32 (quin, J=7.4 Hz, 2H),2.90-3.08 (m, 5H), 3.42-3.67 (m, 7H), 3.77-3.96 (m, 1H), 4.02 (t, J=7.4Hz, 4H), 5.20 (s, 1H), 5.52 (br. s., 1H), 5.63 (s, 1H), 7.28-7.39 (m,1H), 7.57-7.68 (m, 2H), 8.49 (s, 1H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)-N-isopropylpiperazine-1-carboxamideP54

Compound P53 (550 mg, 1.058 mmol) was suspended in dioxane and hunig'sbase was added. The resulting mixture was stirred for 10 minutes. The2-isocyanatopropane (125 μL, 1.269 mmol) was then added at roomtemperature. The mixture was stirred overnight at room temperature. Tothe solution was added an excess of MeOH and the mixture was stirredovernight. The solvent was evaporated. The residue was dissolved indichloromethane (50 ml) and the resulting solution was washed with waterthree times (20 ml). The water layers were extracted withdichloromethane. The combined organic layers were dried over MgSO4 andfiltered. The solvent was removed and the residue was triturated indiethyl ether and stirred overnight in this solvent. The white lightpowder was filtered and dried in the oven at 50° C. to yield (85 mg,14%) of product P54.

m/z=569 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11 (d, J=6.4 Hz, 6H), 1.52 (br. s.,1H), 1.66 (d, J=9.9 Hz, 2H), 1.84 (br. s., 1H), 2.21 (br. s., 2H), 2.28(dt, J=14.5, 7.2 Hz, 2H), 2.85 (br. s, 3H), 3.30-3.62 (m, 10H),3.73-3.86 (m, 1H), 3.98 (t, J=7.3 Hz, 4H), 5.19 (s, 1H), 5.42-5.81 (m,3H), 7.30 (d, J=5.7 Hz, 1H), 7.50-7.70 (m, 2H), 8.46 (s, 1H)

Synthesis of4-(2-(5-(azetidin-1-yl)-7-(4-(methylsulfonyl)piperazin-1-yl)pyrazolo-[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-5-methylquinazolineP55

Compound P53 (500 mg, 1.03 mmol) was dissolved in dichloromethane (25mL) and diisopropylethyl amine (0.445 mL, 2.58 mmol) was added. Theresulting mixture was stirred at room temperate for 10 minutes thenmethanesulfonyl chloride (0.2 mL, 1.55 mmol) was added. The resultingmixture was stirred at room temperature overnight. The resulting mixturewas poured in water, extracted with dichloromethane, dried over MgSO4and concentrated. The resulting residue was purified by columnchromatography using dichloromethane and methanol as eluent to yieldcompound P55 71% pure. This was further purified by HPLC to yield (28mg, 5%) of compound P55 as a white solid.

m/z=562 (M+H)⁺

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (br. s., 1H), 1.65-1.77 (m, 2H),1.78-1.94 (m, 1H), 2.20-2.27 (m, 2H), 2.27-2.38 (m, 2H), 2.87 (s, 3H),2.91 (s, 3H), 3.22-3.35 (m, 4H), 3.44-3.68 (m, 6H), 4.02 (t, J=7.4 Hz,4H), 5.26 (s, 1H), 5.49 (br. s., 1H), 5.67 (br. s., 1H), 7.30-7.36 (m,1H), 7.58-7.67 (m, 2H), 8.49 (s, 1H)

Synthesis of7-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-2-methyloxazolo[5,4-d]pyrimidineP56

Synthesis of 7-chloro-2-methyloxazolo[5,4-d]pyrimidine 71

Step 1: synthesis of 2-methyloxazolo[5,4-d]pyrimidin-7-ol 71-b

A solution of 5-aminopyrimidine-4,6-diol 71-a (5 g, 39 mmol) in aceticanhydride (80 mL) was heated at 120° C. for 16 hours. The solution wasthen cooled and the solid filtered off and triturated with Et₂O. Afterfiltration the solid was dried in the oven to yield the intermediate71-b (4 g, 68%).

m/z=152 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.54 (s, 3H) 8.18 (s, 1H) 12.84 (br. s.,1H)

Step 2: synthesis of 7-chloro-2-methyloxazolo[5,4-d]pyrimidine 71

The intermediate 71-b (100 mg, 0.66 mmol) was dissolved in acetonitrile(20 mL) under inert atmosphere. DIPEA (0.28 mL, 2.5 eq.) and POCl₃ (0.15mL, 2.5 eq.) were added dropwise and the mixture was heated to 70° C.After 3 hours, the solution was concentrated in vacuo, extracted withethyl acetate and washed with saturated NaHCO₃ solution. The combinedorganic layers were dried over MgSO₄, filtered and used as such into thenext step.

LCMS m/z=170 (M+H)

Synthesis of7-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-2-methyloxazolo[5,4-d]pyrimidineP56

To a solution of intermediate 71 (20 mg, 0.12 mmol) in iPrOH (2 mL) wasadded triethyl amine (0.05 mL, 0.35 mmol, 3 eq.) and intermediate 8 (40mg, 0.12 mmol, 1 eq.). The solution underwent microwave irradiationduring 3 hours at 120° C. The resulting solution was concentrated invacuo and purified by Prep HPLC to yield the title compound P56 (21 mg,37%) as a white solid.

m/z=476 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.49-1.79 (m, 4H) 1.84-2.02 (m, 1H)2.20-2.34 (m, 2H) 2.40 (br. s., 1H) 2.53 (s, 3H) 3.15-3.27 (m, 1H)3.36-3.54 (m, 4H) 3.55-3.69 (m, 4H) 3.99 (t, J=7.70 Hz, 4H) 4.99 (d,J=13.32 Hz, 1H) 5.22 (s, 1H) 5.73 (s, 1H) 6.53 (d, J=5.65 Hz, 1H) 8.24(s, 1H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(6-methyl-2-(methylthio)quinazolin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP57

Intermediate 8 (1000 mg, 2.41 mmol),4-chloro-6-methyl-2-(methylthio)quinazoline 72 (649.2 mg, 2.89 mmol) andDIPEA (0.83 ml, 4.8 mmol) were mixed in 2-methoxy-ethanol (30 ml) andheated at 50° C. for 16 hours. The reaction mixture was allowed to cooldown to room temperature and poured in iced watered solution. A solidwas formed this was filter off. The solid was dissolved indichloromethane and the solution obtained was successively dried overMgSO4 and concentrated. The residue was purified by columnchromatography to yield P57 (1.2 g, 78% pure).

m/z=531 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.69 (br. s., 4H), 2.04 (dd, J=13.1, 5.2Hz, 1H), 2.24-2.38 (m, 3H), 2.40 (s, 3H), 2.48 (s, 3H), 3.37-3.41 (m,1H), 3.49 (t, J=4.5 Hz, 4H), 3.62-3.76 (m, 4H), 4.00 (t, J=7.5 Hz, 4H),4.13 (d, J=13.2 Hz, 1H), 5.30 (s, 1H), 5.82 (d, J=2.2 Hz, 1H), 5.93 (s,1H), 7.76 (s, 1H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(5-ethylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP58

Synthesis of 4-chloro-5-ethylquinazoline 73

Step 1: synthesis of 5-ethylquinazolin-4-ol 73-b

A mixture of 2-amino-6-ethylbenzoic acid 73-a (18.0 g, 109 mmol) informamide (200 ml) was stirred at 130° C. for 16 hours. The mixture wascooled to room temperature. The precipitate was filtered off and washedwith water. The filter cake was dried in vacuum at 45° C. for 1 hour.The resulting solid intermediate 73-b was recovered (8.5 g, purity: 90%,yield: 40.3%).

Step 2: synthesis of 4-chloro-5-ethylquinazoline 73

Triethylamine (19.51 ml, 140.0 mmol) was added to a mixture of5-ethylquinazolin-4 ol 73-b (7.0 g, 40 mmol) in phosphorus oxychloride(100 ml) at 0° C. The resulting mixture was refluxed for 3 hours. Thesolvent was evaporated under vacuum. The residue was dissolved intoluene (100 ml) and the mixture was added dropwise into ice (100 g).The organic layer was washed successively with water (2×100 ml), 10%sodium bicarbonate solution (2×100 ml), water (2×100 ml) and brine(1×100 ml). The organic layer was dried (Na₂SO₄), filtered and thefiltrate was concentrated under vacuum. The residue was purified byflash column chromatography over silica gel (eluent: petroleumether/ethyl acetate 10/1 to give intermediate 73 (3.313 g, purity: 96%,yield: 41.37%).

¹H NMR (400 MHz, CDCl₃) δ ppm 1.39 (t, J=7.46 Hz, 3H) 3.48 (q, J=7.34Hz, 2H) 7.56 (d, J=7.34 Hz, 1H) 7.84 (t, J=7.83 Hz, 1H) 7.95 (d, J=8.31Hz, 1H) 8.96 (s, 1H)

Step 3: synthesis of4-(5-(azetidin-1-yl)-2-(1-(5-ethylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP58

The mixture of intermediate 8 HCl salt (500 mg, 1.2 mmol) andintermediate 73 (348 mg, 1.5 mmol) was dissolved in 2-methoxyethanol (15ml) and triethyl amine (0.415 ml, 2.4 mmol) was added. The resultingmixture was stirred at 50° C. for 16 hours. The reaction mixture wasallowed to cool down to room temperature and poured in iced wateredsolution. The resulting mixture was stirred until the ice melt thenfiltered off and the solid was washed with water. The solid wasdissolved in dichloromethane, dried over MgSO4 and concentrated. Thesolid was purified by column chromatography using dichloromethane andmethanol to yield P58 as a white powder (400 mg, 63%).

m/z=499 (M+H)⁺

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.23 (m, 3H), 1.42-1.57 (m, 1H),1.66 (d, J=8.1 Hz, 2H), 1.73-1.91 (m, 1H), 2.06-2.35 (m, 4H), 3.10-3.41(m, 3H), 3.40-3.55 (m, 5H), 3.58-3.78 (m, 5H), 3.89-4.06 (m, 4H), 5.18(s, 1H), 5.35-5.66 (m, 2H), 7.37 (d, J=7.0 Hz, 1H), 7.50-7.68 (m, 2H),8.43 (s, 1H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(5,7-dimethylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP59

Synthesis of 4-chloro-5,7-dimethylquinazoline 74

Step 1: synthesis of(E)-N-(3,5-dimethylphenyl)-2-(hydroxyimino)acetamide 74-b

Sodium sulfate (390.7 g, 2.750 mol) was added into a solution of chloralhydrate (76.5 g, 0.520 mol) in water (1500 mL) at room temperature.Then, a suspension of hydroxylamine hydrochloride (91.8 g, 1.32 mol),3,5-dimethylaniline 74-a (50 g, 0.41 mol) and concentrated hydrochloricacid (36.5%, 50 mL) was added. The mixture was heated at 45° C. for 1.5hours, then 75° C. for 1 hour. The reaction mixture was cooled to roomtemperature. The precipitated brown solid was filtered and washed withcold water and hexane. The crude compound was dried under vacuum to giveintermediate 74-b (70 g, yield: 83.78%).

Step 2: synthesis of 4,6-dimethylindoline-2,3-dione 74-c

Intermediate 74-b (15.00 g, 78.04 mmol) was dissolved in concentratedsulfuric acid (75 ml). The mixture was stirred at 80° C. for 30 minutes.Then the mixture was cooled to room temperature and poured into icewater. Intermediate 75-c was precipitated, filtered and washed withwater (8.50 g, 49.74%).

Step 3: synthesis of 2-amino-4,6-dimethylbenzoic acid 74-d

H₂O₂ (123.7 g, 1200 mmol) was added to a mixture of intermediate 74-C(35.00 g, 199.8 mmol) in NaOH solution (1225 mL, 0.33 g/mL) at 70° C.,over 5 minutes. The mixture was heated for another 15 minutes, thencooled to 15° C. Ice was added to the mixture. The resulting mixture wasextracted with ethyl acetate (300 mL×2). The pH of the solution wasadjusted to 8 with addition of concentrated HCl at 0° C. and acidifiedto pH ˜6 with acetic acid. The mixture was extracted with ethyl acetate(300 mL×2). The organic layers were combined, washed with brine, driedover MgSO₄ and filtered. The filtrate was concentrated to giveintermediate 74-d (17 g, yield: 41.20%).

Step 4: synthesis of 5,7-dimethylquinazolin-4-ol 74-e

A mixture of intermediate 74-d (15.0 g, 90.8 mmol) and formamidineacetate (94.5 g, 908 mmol) was stirred for 5 hours at 150° C. H₂O wasadded to the mixture and the mixture was stirred 10 minutes at roomtemperature. The precipitate was filtered off and washed with water. Thefilter cake was dried under vacuum to give intermediate 74-e (17.5 g,yield: 39.83%).

Step 5: synthesis of 4-chloro-5,7-dimethylquinazoline 74

Triethylamine (30.50 ml, 301.4 mmol) was added to a mixture ofintermediate 74-e (17.50 g, 100.5 mmol) in POCl₃ (300 g, 1.96 mol) at 0°C. The resulting mixture was refluxed for 3 hours then was poured intoice water. The resulting mixture was extracted with ethyl acetate. Theorganic layer was washed with NaHCO₃ solution (1%) and brine, dried overMgSO₄ and filtered. The filtrate was concentrated. The crude product waspurified by chromatography over silica gel (eluent: hexanes/ethylacetate from 0/1 to 1:1). The desired fractions were collected andconcentrated to give intermediate 74 (4.806 g, 23.69%).

¹H NMR (400 MHz, CDCl₃) δ ppm 2.53 (s, 3H) 3.00 (s, 3H) 7.34 (s, 1H)7.71 (s, 1H) 8.90 (s, 1H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(5,7-dimethylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP59

The mixture of intermediate 8 TFA salt (300 mg, 0.66 mmol) andintermediate 74 (177 mg, 0.92 mmol) was dissolved in 2-methoxyethanol(15 ml) and triethyl amine (0.34 ml, 1.97 mmol) was added. The resultingmixture was stirred at 50° C. for 16 hours. The reaction mixture wasallowed to cool down to room temperature and poured in iced wateredsolution. The resulting mixture was stirred until the ice melt thenfiltered off and the solid was washed with water. The solid wasdissolved in dichloromethane dried over MgSO4 and concentrated. Thesolid was purified by column chromatography using dichloromethane andmethanol to yield P59 as a white powder (212 mg, 64%).

m/z=499 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.52 (br. s., 1H), 1.65 (d, J=5.1 Hz,2H), 1.74-1.90 (m, 1H), 2.17 (br. s., 2H), 2.28 (quin, J=7.3 Hz, 2H),2.41 (s, 3H), 2.80 (s, 3H), 3.35-3.58 (m, 6H), 3.60-3.77 (m, 4H), 3.98(t, J=7.3 Hz, 4H), 5.17 (s, 1H), 5.41 (br. s., 1H), 5.53-5.73 (m, 1H),7.14 (s, 1H), 7.38 (s, 1H), 8.42 (s, 1H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(5-fluoroquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP60

The mixture of intermediate 8 TFA salt (400 mg, 0.87 mmol) and4-chloro-5-fluoro-quinazoline 75 (208 mg, 1.14 mmol) was dissolved in2-methoxyethanol (20 ml) and triethyl amine (0.604 ml, 3.5 mmol) wasadded. The resulting mixture was stirred at 50° C. for 2 hours. Thereaction mixture was allowed to cool down to room temperature and pouredin iced watered solution. The resulting mixture was stirred until theice melt then filtered off and the solid was washed with water. Thesolid was dissolved in dichloromethane, dried over MgSO4 andconcentrated to yield a white solid P60 (145 mg, 34%).

m/z=489 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.57-1.90 (m, 4H), 2.06-2.20 (m, 1H),2.26-2.43 (m, 3H), 3.38-3.51 (m, 1H), 3.54 (br. s., 4H), 3.65-3.79 (m,4H), 3.92 (d, J=12.8 Hz, 1H), 4.02 (t, J=7.4 Hz, 4H), 5.23 (s, 1H), 5.75(s, 1H), 5.80 (br. s., 1H), 7.23 (dd, J=11.7, 7.9 Hz, 1H), 7.61 (d,J=8.4 Hz, 1H), 7.68-7.79 (m, 1H), 8.51 (s, 1H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(5-ethoxyquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP61

Synthesis of 4-chloro-5-ethoxyquinazoline 76

Step 1: synthesis of 5-ethoxyquinazolin-4-ol 76-b

Sodium hydride (8.00 g, 200 mmol, 60% in mineral oil) was added toethanol (300 ml) at 0° C. After stirred for 30 min at 0° C.5-bromoquinazolin-4-ol 76-a (15.00 g, 66.65 mmol) and cupper (1.70 g,26.7 mmol) were added. The reaction mixture was stirred at 80° C. for 18h and then cooled to room temperature. The mixture was filtered througha pad of Celite. The filtrate was concentrated in vacuum. The residuewas taken up in water and the pH was adjusted to 8 by addition of asolution of hydrochloric acid 37%. The solution was extracted withCH₂Cl₂. The organic phase was dried over Na₂SO₄, filtered and evaporatedin vacuum. The residue was purified by column chromatography over silicagel (eluent: petroleum ether/ethyl acetate 2/1) to afford intermediate76-b (5 g, yield: 35%).

Step 2: synthesis of 4-chloro-5-ethoxyquinazoline 76

Oxalyl chloride (12.5 mmol) was added dropwise to a solution ofintermediate 76-b (5.00 g, 26.3 mmol) and DMF (2.5 ml) in CH₃Cl (100ml). The solution was refluxed overnight. The reaction solution wasconcentrated under vacuum. The residue was purified over silica gel on aglass filter (eluent: CH₂Cl₂/ethyl acetate 1/1). The desired fractionswere collected and the solvent was evaporated to afford intermediate 77(2.81 g, yield: 49%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.48 (m, 3H) 4.14-4.23 (m, 2H)7.15-7.23 (m, 1H) 7.27-7.36 (m, 1H) 7.77-7.87 (m, 1H) 8.90 (s, 1H) Themixture of intermediate 8 TFA salt (500 mg, 1.1 mmol) and4-chloro-5-ethoxyquinazoline 76 (320 mg, 1.5 mmol) was dissolved in2-methoxyethanol (20 ml) and triethyl amine (0.566 ml, 3.3 mmol) wasadded. The resulting mixture was stirred at 50° C. for 4 days. Thereaction mixture was allowed to cool down to room temperature and pouredin iced watered solution. The resulting mixture was stirred until theice melt then filtered off and the solid was washed with water. Thesolid was dissolved in dichloromethane dried over MgSO4 and concentratedto yield a residue that was purified by preparative HPLC to yield P61 asa white solid (76 mg, 13%).

m/z=515 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.49 (m, 3H), 1.51-1.92 (m, 4H),2.08-2.24 (m, 1H), 2.25-2.43 (m, 3H), 3.27-3.47 (m, 1H), 3.48-3.63 (m,4H), 3.65-3.82 (m, 4H), 3.87-4.10 (m, 5H), 4.15-4.35 (m, 2H), 5.22 (s,1H), 5.67 (br. s., 1H), 5.83 (br. s., 1H), 6.98 (d, J=7.7 Hz, 1H), 7.31(d, J=8.1 Hz, 1H), 7.55-7.69 (m, 1H), 8.38 (br. s., 1H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(5-(trifluoromethyl)quinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP62

Synthesis of 4-chloro-5-(trifluoromethyl)quinazoline 77

Step 1: synthesis of 5-(trifluoromethyl)quinazolin-4(3H)-one 77-b

A mixture of 2-amino-6-(trifluoromethyl)benzoic acid 77-a (9.00 g, 43.9mmol) and formamidine acetate (22.84 g, 219.4 mmol) in n-butanol (180ml) was stirred at 100° C. for 5 hours. The solvent was evaporated undervacuum. The residue was washed with ethanol (2×50 ml) and then dried invacuum at 45° C. for 1 hour to give intermediate 77-b (9 g, yield: 91%).

Step 2: synthesis of 4-chloro-5-(trifluoromethyl)quinazoline 77

Triethyl amine (29.3 ml, 210 mmol) was added to a mixture ofintermediate 77-b (8.00 g, 37.4 mmol) in phosphorus oxychloride (331 g,2.16 mol) at 0° C. The mixture was refluxed for 2 hours. The solvent wasevaporated under vacuum. The residue was dissolved in ethyl acetate (200ml) and the mixture was added to ice (200 g). The separated organiclayer was washed successively with water (1×100 ml), 10% sodiumbicarbonate aqueous solution (2×100 ml), water (1×100 ml) and brine(1×100 ml). The separated organic layer was dried over sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography over silica gel (eluent: petroleum ether/ethylacetate 1/0 to 1/1) to give intermediate 77 (7.97 g, 91.38%).

¹H NMR (400 MHz, CDCl₃) δ ppm 7.89-8.06 (m, 1H) 8.22 (d, J=7.50 Hz, 1H)8.31 (d, J=8.38 Hz, 1H) 9.11 (s, 1H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(5-(trifluoromethyl)quinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP62

The mixture of intermediate 8 TFA salt (300 mg, 0.65 mmol), intermediate77 (183 mg, 0.78 mmol) was dissolved in 2-methoxyethanol (20 mL) thendiisopropylethyl amine (0.45 mL, 2.6 mmol) was added. The resultingmixture was stirred at 50° C. overnight. The mixture was allowed to cooldown to room temperature and poured in iced watered solution. Theresulting mixture was stirred until all the ice is melt then theresulting solid was filtered off. The solid was successively washed withwater, dissolved in dichloromethane, dried over MgSO4 and concentratedto yield P62 (250 mg, 70%) as a white light solid.

m/z=539 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.37-1.60 (m, 1H), 1.69 (br. s., 2H),1.82 (d, J=11.9 Hz, 1H), 2.07-2.40 (m, 4H), 3.32-3.59 (m, 5H), 3.62-3.80(m, 5H), 4.02 (t, J=7.4 Hz, 4H), 5.20 (s, 1H), 5.46-5.70 (m, 2H),7.81-7.91 (m, 2H), 7.94-8.01 (m, 1H), 8.49 (s, 1H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(6-ethyl-5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP63

Synthesis of 4-chloro-6-ethyl-5-methylquinazoline 78

Step 1: synthesis of 6-iodo-5-methylquinazolin-4-ol 78-b

A solution of 6-amino-3-iodo-2-methylbenzoic acid 78-a (35.0 g, 126mmol) and formamidine acetate (59.0 g, 567 mmol) in EtOH (500 ml) wasrefluxed overnight. The precipitate was filtered off and washed withethanol to afford intermediate 78-b (21 g, yield 52%).

Step 2: synthesis of 5-methyl-6-vinylquinazolin-4-ol 78-c

A solution of intermediate 78-b (15.0 g, 52.4 mmol), potassiumtrifluoro(vinyl)borate (10.6 g, 79.0 mmol), Pd(dppf)₂Cl₂ (1.7 g, 2.6mmol) and K₂CO₃ (21.74 g, 157.3 mmol) in EtOH (150 ml) was refluxedovernight. The solvent was evaporated under vacuum. The residue wastreated with H₂O and CH₂Cl₂. The separated organic layer was dried overMgSO4, filtrated and evaporated under vacuum. The residue was purifiedby high-performance liquid chromatography over SYNERGI (eluent: TFAwater/acetonitrile 30/70 v/v). The product fractions were collected andthe organic solvent was evaporated. The pH was adjusted to 7 withsaturated NaHCO₃. The aqueous concentrate was extracted with CH₂Cl₂. Theseparated organic layer was concentrated under vacuum to affordintermediate 78-c (3 g, yield 29%).

Step 3: synthesis of 6-ethyl-5-methylquinazolin-4-ol 78-d

A solution of intermediate 78-c (3.0 g, 16 mmol) and HCl (11.5 ml) inMeOH (30 ml) was hydrogenated at room temperature (50 psi) with Pd/C(0.6 g) as a catalyst for 15 hours. After uptake of H₂ (32.50 mg, 16.11mmol), the catalyst was filtered off and washed with methanol. Thesolvent was evaporated under vacuum to afford intermediate 78-d (2.1 g,yield 66%).

Step 4: synthesis of 4-chloro-6-ethyl-5-methylquinazoline 78

A mixture of intermediate 78-d (1.80 g, 9.56 mmol), triethylamine (2.220ml, 15.95 mmol) and phosphorus oxychloride (60 ml) was refluxed for 2hours. The solvent was evaporated under vacuum. The residue wasdissolved in ethyl acetate (200 ml) and the mixture was added drop wiseinto ice (200 g). The separated organic layer was washed successivelywith water (1×100 ml), 10% sodium bicarbonate aqueous solution (2×100ml), water (1×100 ml) and brine (1×100 ml). The organic layer was dried(MgSO₄), filtered and the filtrate was concentrated under vacuum. Theresidue was purified by column chromatography over silica gel (eluent:petroleum ether/ethyl acetate 1/0 to 5/1) to give intermediate 78 (1.434g, 68.94%).

¹H NMR (400 MHz, CDCl₃) δ ppm 1.27 (t, J=7.65 Hz, 3H) 2.88 (q, J=7.53Hz, 2H) 2.94 (s, 3H) 7.75 (d, J=8.53 Hz, 1H) 7.87 (d, J=8.53 Hz, 1H)8.89 (s, 1H)

Step 5: synthesis of4-(5-(azetidin-1-yl)-2-(1-(6-ethyl-5-methylquinazolin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP63

The mixture of intermediate 8 TFA salt (400 mg, 0.87 mmol), intermediate78 (235 mg, 1.14 mmol) was dissolved in 2-methoxyethanol (20 mL) thendiisopropylethyl amine (0.604 mL, 3.5 mmol) was added. The resultingmixture was stirred at 50° C. for 4 days. The mixture was allowed tocool down to room temperature and poured in iced watered solution. Theresulting mixture was stirred until all the ice is melt then theresulting solid was filtered off. The solid was successively washed withwater, dissolved in dichloromethane, dried over MgSO4 and concentratedthe residue was purified by preparative HPLC to yield P63 (198 mg, 44%)as a white light solid.

m/z=513 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26 (t, J=7.5 Hz, 3H), 1.37-1.58 (m,1H), 1.67 (br. s., 2H), 1.77-1.94 (m, 1H), 2.12-2.39 (m, 6H), 2.75-2.89(m, 6H), 3.52 (br. s., 5H), 3.65-3.80 (m, 4H), 4.02 (t, J=7.4 Hz, 4H),5.21 (s, 1H), 5.61 (s, 2H), 7.49-7.63 (m, 2H), 8.40 (s, 1H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(5,6-dimethylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP64

Synthesis of 4-chloro-5,6-dimethylquinazoline 79

Step 1: synthesis of 5,6-dimethylquinazolin-4-ol 79-a

PdCl₂(dppf)₂ (114 mg, 0.180 mmol) and PPh₃ (183 mg, 0.700 mmol) wereadded to a mixture of intermediate 78-b (1.0 g, 3.5 mmol), Me₄Sn (940mg, 5.20 mmol) and CuI (67 mg, 0.35 mmol) in NMP (15 ml) under N₂. Themixture was stirred under microwave at 150° C. for 0.5 hours. Theresulting mixture was poured into water. The precipitate was filteredoff and concentrated under vacuum. The residue was purified by columnchromatography over silica gel (eluent: methanol/ethyl acetate 1/10) toafford intermediate 79-a (0.7 g, yield: 27%).

Step 2: synthesis of 4-chloro-5,6-dimethylquinazoline 79

A mixture of intermediate 79-a (700 mg, 4.02 mmol), phosphorusoxychloride (20 ml) and triethylamine (2.80 ml, 20.1 mmol) was refluxedfor 2 hours. The solvent was evaporated under vacuum. The residue wasdissolved in ethyl acetate (50 ml) and the mixture was added to ice (20g). The separated organic layer was successively washed with water (1×20ml), 10% sodium bicarbonate aqueous solution (2×20 ml), water (1×20 ml)and brine (1×20 ml). The organic layer was dried over magnesium sulfate,filtered, concentrated under vacuum. The residue was purified by columnchromatography over silica gel (eluent: petroleum ether/ethyl acetate1/0 to 10/1) to give intermediate 79 (598.30 mg, 73%).

¹H NMR (400 MHz, CDCl₃) δ ppm 2.53 (s, 3H) 2.92 (s, 3H) 7.68-7.78 (m,1H) 7.80-7.89 (m, 1H) 8.89 (s, 1H).

Step 3: synthesis of4-(5-(azetidin-1-yl)-2-(1-(5,6-dimethylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP64

The mixture of intermediate 8 TFA salt (300 mg, 0.65 mmol), intermediate79 (183 mg, 0.95 mmol) was dissolved in 2-methoxyethanol (15 mL) thendiisopropylethyl amine (0.45 mL, 2.6 mmol) was added. The resultingmixture was stirred at 50° C. for three days. The mixture was allowed tocool down to room temperature and poured in iced watered solution. Theresulting mixture was stirred until all the ice is melt then theresulting solid was filtered off. The solid was successively washed withwater, dissolved in dichloromethane, dried over MgSO4 and concentratedto yield compound P64 (150 mg, 45%) as a white light solid.

m/z=499 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.67 (br. s., 3H), 1.82 (d, J=11.7 Hz,1H), 2.09-2.37 (m, 4H), 2.41 (s, 3H), 2.67-2.86 (m, 4H), 3.52 (br. s.,5H), 3.65-3.83 (m, 4 H), 4.02 (t, J=7.4 Hz, 4H), 5.21 (s, 1H), 5.40-5.90(m, 2H), 7.48-7.59 (m, 2H), 8.40 (s, 1H)

Synthesis of7-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-2-methyloxazolo[5,4-d]pyrimidineP65

To a solution of intermediate 71 (20 mg, 0.12 mmol) in iPrOH (2 mL) wasadded triethyl amine (0.05 mL, 0.35 mmol, 3 eq.) and intermediate 8 (40mg, 0.12 mmol, 1 eq.). The solution underwent microwave irradiationduring 3 hours at 120° C. The resulting solution was concentrated invacuum and purified by Prep HPLC to yield the title compound P65 (21 mg,37%) as a white solid.

m/z=476 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.49-1.79 (m, 4H) 1.84-2.02 (m, 1H)2.20-2.34 (m, 2H) 2.40 (br. s., 1H) 2.53 (s, 3H) 3.15-3.27 (m, 1H)3.36-3.54 (m, 4H) 3.55-3.69 (m, 4H) 3.99 (t, J=7.70 Hz, 4H) 4.99 (d,J=13.32 Hz, 1H) 5.22 (s, 1H) 5.73 (s, 1H) 6.53 (d, J=5.65 Hz, 1H) 8.24(s, 1H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(5,8-dimethylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP66

The mixture of intermediate 8 TFA salt (300 mg, 0.65 mmol),4-chloro-5,8-dimethyl-quinazoline 80 (175 mg, 0.9 mmol) was dissolved in2-methoxyethanol (15 mL) then diisopropylethyl amine (0.45 mL, 2.6 mmol)was added. The resulting mixture was stirred at 50° C. for three days.The mixture was allowed to cool down to room temperature and poured iniced watered solution. The resulting mixture was stirred until all theice is melt then the resulting solid was filtered off. The solid wasn'tpure it was dissolved in dichloromethane the water layer was extractedwith dichloromethane all the organics were combined and dried overMgSO4.

The solvent was removed and the residue was purified by columnchromatography using dichloromethane and methanol. The compound P66 wasisolated as a white solid (150 mg, 46%).

m/z=499 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51 (br. s., 1H), 1.64 (d, J=7.7 Hz,2H), 1.82 (d, J=7.9 Hz, 1H), 2.18 (br. s., 2H), 2.28 (quin, J=7.4 Hz,2H), 2.56 (s, 3H), 2.78 (s, 3H), 3.35-3.56 (m, 6H), 3.61-3.74 (m, 4H),3.98 (t, J=7.4 Hz, 4H), 5.17 (s, 1H), 5.46 (br. s., 1H), 5.62 (br. s.,1H), 7.18 (d, J=7.3 Hz, 1H), 7.46 (d, J=7.3 Hz, 1H), 8.50 (s, 1H)

Synthesis of methyl4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-5-methylquinazoline-2-carboxylateP67

Intermediate 15 (100 mg, 0.13 mmol) was dissolved in 30 mL THF/MeOH(3/1) in an autoclave. Potassium acetate (20 mg, 0.20 mmol, 1.5 eq.),Pd(OAc)₂ (3 mg, 0.013 mmol, 0.1 eq.) and1,3-bis(diphenylphosphino)propane (11 mg, 0.027 mmol, 0.2 eq.) wereadded. The autoclave was heated to 120° C. under 50 bar carbon monoxidepressure during 8 hours. After cooling to room temperature the solutionwas concentrated in vacuum and diluted with DCM then washed withsaturated solution of NaHCO₃. The combined organics were dried withMgSO₄, filtered off and concentrated in vacuum. The crude was furtherpurified on HPLC giving methyl compound P67 (43 mg, 60%).

m/z=543 (M+H)⁺

¹H NMR (400 MHz, 420 K, DMSO-d₆) δ ppm 1.42-1.59 (m, 1H) 1.62-1.70 (m,2H) 1.77-1.88 (m, 1H) 2.14-2.33 (m, 4H) 2.80 (s, 3H) 3.43-3.55 (m, 5H)3.64-3.74 (m, 5H) 3.85 (s, 3H) 3.99 (t, J=7.41 Hz, 4H) 5.18 (s, 1H) 5.61(m, J=3.98 Hz, 1H) 5.66 (s, 1H) 7.39 (t, J=4.22 Hz, 1H) 7.66 (d, J=4.30Hz, 2H)

Synthesis of4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-5-methylquinazoline-2-carboxylicacid P68

To a solution of compound P67 (300 mg, 0.38 mmol) in 30 mL THF/water(3/1) was added LiOH (28 mg, 1.16 mmol, 3 eq.). The reaction mixture wasstirred for 2 days at room temperature. The reaction mixture was thenadjusted to pH=6 with HCl (1M in water) and concentrated in vacuum. Thecrude was purified on HPLC to give compound P68 (110 mg, 53%).

m/z=529 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.44-1.62 (m, 1H) 1.64-1.76 (m, 2H)1.78-1.91 (m, 1H) 2.16-2.37 (m, 4H) 3.24 (s, 3H) 3.46-3.59 (m, 5H)3.68-3.77 (m, 5H) 4.02 (t, J=7.37 Hz, 4H) 5.22 (s, 1H) 5.54-5.88 (m, 2H)7.39-7.44 (m, 1H) 7.68-7.73 (m, 2H)

Synthesis of4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-5-methyl-N-(methylsulfonyl)quinazoline-2-carboxamideP69

Compound P68 (150 mg, 0.28 mmol) was dissolved in 10 mL THF and CDI (92mg, 0.56 mmol, 2 eq.) was added. The mixture was heated to 50° C. andafter one hour stirring, DBU (0.08 mL, 0.56 mmol, 2 eq.) and methylsulfonamide (70 mg, 0.74 mmol, 2.6 eq.) were added to the solution.After 1 hour stirring at 50° C. the solution was concentrated in vacuumand purified by column chromatography eluting with a gradient startingfrom 0% to 10% MeOH in DCM giving compound P69 (65 mg, 38%).

m/z=606 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46-1.60 (m, 1H) 1.62-1.73 (m, 2H)1.77-1.89 (m, 1H) 2.15-2.38 (m, 4H) 2.80 (s, 3H) 3.27 (s, 3H) 3.42-3.60(m, 5H) 3.64-3.77 (m, 5H) 4.00 (t, J=7.42 Hz, 4H) 5.20 (s, 1H) 5.68-5.77(m, 2H) 7.38-7.47 (m, 1H) 7.65-7.76 (m, 2H)

Synthesis of4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-N,5-dimethylquinazoline-2-carboxamideP70

To a solution of compound P68 (240 mg, 0.45 mmol) in DMF (5 mL) wasadded DIPEA (0.23 mL, 1.36 mmol, 3 eq.), methyl amine (0.08 mL, 0.90mmol, 2 eq.) and HATU (431.5 mg, 1.135 mmol, 2.5 eq.). The resultingsolution was stirred for 1 hour at room temperature. Water (5 mL) wasadded and the solution was concentrated in vacuum and purified on HPLCto give compound P70 (87 mg, 36%).

m/z=542 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.45-1.60 (m, 1H) 1.67 (br. s., 2H)1.76-1.90 (m, 1H) 2.10-2.24 (m, 2H) 2.28 (quin, J=7.37 Hz, 2H) 2.79-2.87(m, 6H) 3.35-3.62 (m, 6H) 3.61-3.75 (m, 4H) 3.98 (t, J=7.37 Hz, 4H) 5.19(s, 1H) 5.54 (br. s., 1H) 5.68 (br. s., 1H) 7.29-7.42 (m, 1H) 7.58-7.72(m, 2H) 8.04 (br. s., 1H)

Synthesis of4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-N-(cyclopropylsulfonyl)-5-methylquinazoline-2-carboxamideP71

Compound P68 (150 mg, 0.28 mmol) was dissolved in 10 mL THF and CDI (92mg, 0.56 mmol, 2 eq.) was added. The mixture was heated to 50° C. andafter one hour stirring, DBU (0.12 mL, 0.85 mmol, 3 eq.) and cyclopropylsulfonamide (85 mg, 0.709 mmol, 2.5 eq.) were added to the solution.After 1 hour stirring at 50° C. the solution was concentrated in vacuumand purified by column chromatography eluting with a gradient startingfrom 0% to 10% MeOH in DCM and further purified on HPLC giving compoundP71 (65 mg, 44%).

m/z=632 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.99-1.10 (m, 2H) 1.13-1.26 (m, 2H)1.44-1.93 (m, 4H) 2.12-2.35 (m, 4H) 2.81 (s, 3H) 2.95-3.02 (m, 1H)3.41-3.60 (m, 5H) 3.63-3.75 (m, 5H) 3.99 (t, J=7.42 Hz, 4H) 5.19 (s, 1H)5.65-5.77 (m, 2H) 7.42 (d, J=6.67 Hz, 1H) 7.67-7.75 (m, 2H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(2-(isoxazol-4-yl)-5-methylquinazolin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP72

Intermediate 15 (200 mg, 0.369 mmol), isoxazol-4-ylboronic acid(cas=1008139-25-0, 83 mg, 0.738 mmol) and K₂CO₃ (cas=584-08-7, 102 mg,0.738 mmol) were dissolved in 1,4-dioxane (3 ml) and water (0.3 ml). Thesolution was degazed by N₂ for 5 minutes. The reaction tube was sealedand the mixture was heated at 120° C. for 30 minutes in a microwaveoven. Then the solution was diluted with DCM and water. The product wasextracted 2 times with DMC. The organic layers were dried over Na₂SO₄,filtered and evaporated to dryness and the crude was purified by columnchromatography eluting with a gradient of MeOH in DCM, starting with 0%to 5% MeOH. After evaporation of the concerning fractions we get a brownsolid. The solid was triturated in hot DIPE. After cooling to roomtemperature, the precipitate was filtered. Because the product was stillnot pure, the brown solid was triturated once again with hot DIPE. Aftercooling the title compound P72 was obtained by filtration (21 mg, 10%).

m/z=552.3 (M+H).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25-2.46 (m, 8H) 2.66 (s, 3H) 3.24-4.72(m, 14H) 5.09-9.25 (m, 8H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(2-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP73

Compound P73 was prepared in the same manner as compound P72 usingintermediate 15 and1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,2,3-triazoleas starting material.

m/z=580 (M+H).

MP: 238.91° C.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.29-2.05 (m, 4H) 2.12-2.49 (m, 4H)2.55-2.76 (m, 3H) 2.82-3.00 (m, 3H) 3.13-4.16 (m, 14H) 4.30-4.49 (m, 3H)4.93-6.11 (m, 3H) 7.27-7.34 (m, 1H) 7.53-7.79 (m, 2H)

Synthesis of4-(5-(azetidin-1-yl)-2-(1-(5-methoxyquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholineP74

The mixture of intermediate 8 TFA salt (300 mg, 0.65 mmol),4-chloro-5-methoxy-quinazoline 81 (153 mg, 0.78 mmol) was dissolved in2-methoxyethanol (15 mL) then diisopropylethyl amine (0.45 mL, 2.6 mmol)was added. The resulting mixture was stirred at 50° C. overnight. Themixture was allowed to cool down to room temperature and poured in icedwatered solution. The resulting mixture was stirred until all the ice ismelt then the resulting solid was filtered off. The solid wassuccessively washed with water, dissolved in dichloromethane, dried overMgSO4 and concentrated to yield compound P74 (267 mg, 81%) as a whitelight solid.

m/z=501 (M+H).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.58-1.82 (m, 4H), 2.02-2.14 (m, 1H),2.22-2.39 (m, 3H), 3.28-3.41 (m, 1H), 3.45-3.56 (m, 4H), 3.66-3.75 (m,4H), 3.92 (s, 3H), 3.99 (t, J=7.5 Hz, 5H), 5.18 (s, 1H), 5.63 (s, 1H),5.68 (br. s., 1H), 6.95 (d, J=7.5 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.59(t, J=8.1 Hz, 1H), 8.35 (s, 1H).

B. Pharmacological Examples B.1 Antiviral Activity

Black 384-well clear-bottom microtiter plates (Corning, Amsterdam, TheNetherlands) were filled via acoustic drop ejection using the echoliquid handler (Labcyte, Sunnyvale, Calif.). 200 nL of compound stocksolutions (100% DMSO) were transferred to the assay plates. 9 serial4-fold dilutions of compound were made, creating per quadrant the samecompound concentration. The assay was initiated by adding 10 μL ofculture medium to each well (RPMI medium without phenol red, 10%FBS-heat inactivated, 0.04% gentamycin (50 mg/mL). All addition stepsare done by using a multidrop dispenser (Thermo Scientific, Erembodegem,Belgium). Next, rgRSV224 virus (MOI=1) diluted in culture medium wasadded to the plates. rgRSV224 virus is an engineered virus that includesan additional GFP gene (Hallak L K, Spillmann D, Collins P L, Peeples ME. Glycosaminoglycan sulfation requirements for respiratory syncytialvirus infection; Journal of virology (2000), 74(22), 10508-13) and wasin-licensed from the NIH (Bethesda, Md., USA). Finally, 20 μL of a HeLacell suspension (3,000 cells/well) were plated. Medium, virus- andmock-infected controls were included in each test. The wells contain0.05% DMSO per volume. Cells were incubated at 37° C. in a 5% CO2atmosphere. Three days post-virus exposure, viral replication wasquantified by measuring GFP expression in the cells by an in housedeveloped MSM laser microscope (Tibotec, Beerse, Belgium). The EC50 wasdefined as the 50% inhibitory concentration for GFP expression. Inparallel, compounds were incubated for three days in a set of white384-well microtiter plates (Corning) and the cytotoxicity of compoundsin HeLa cells was determined by measuring the ATP content of the cellsusing the ATPlite kit (Perkin Elmer, Zaventem, Belgium) according to themanufacturer's instructions. The CC₅₀ was defined as the 50%concentration for cytotoxicity.

TABLE B-1 antiviral data and selectivity index RSV HELA SI TOX Co. No.pEC₅₀ HELA P1 6.1 4.4 P2 6.5 4.4 P3 5.4 4.6 P4 6.8 <4 P5 6.6 <5 P6 8.3<4.0 P7 5.7 <4 P8 8.1 <4 P9 8.3 <4.6 P10 6.2 <4.3 P11 6.9 <4.6 P12 6.7<4 P13 6.4 4.3 P14 6.1 <4 P15 6.6 4.0 P16 7.1 4.3 P17 8.4 4.4 P18 <6<4.3 P19 8.0 <4.3 P20 6.2 5.4 P21 6.4 <4.6 P22 7.1 4.5 P23 7.8 <4.6 P24<4.6 <4.6 P25 7.5 <4.6 P26 7.6 4.3 P27 6.2 4.5 P28 6.1 <4 P29 6.4 4.5P30 6.2 4.6 P31 6.8 4.8 P32 7.3 <4 P33 7.88 4.2 P34 6.2 4.3 P35 7.2 4.4P36 6.3 <4 P37 6.5 4.3 P40 6.8 4.7 P41 7.1 <4 P42 5.6 <4.6 P43 4.8 4.2P44 6.1 4.2 P45 6.7 4.2 P46 6.5 4.3 P47 6.3 4.6 P48 7.9 4.5 P49 6.1 4.3P50 6.2 4.3 P51 6.5 4.3 P52 7.1 4.7 P53 7.3 4.6 P54 7.6 4.5 P55 7.8 4.3P57 6.2 4.5 P58 6.3 <4 P59 6.4 4.3 P60 6.9 4.3 P61 7.5 <4 P62 7.0 4.3P63 6.4 4.4 P64 7.8 <4.6 P65 7.8 <4.6 P66 7.0 — P67 6.9 <4.3 P68 6.5<4.6 P69 6.5 <4 P70 6.2 4.3 P71 6.4 <4 P72 7.6 4.5 P73 6.9 4.8 P74 7.8<4.6

C. Prophetic Composition Examples

“Active ingredient” as used throughout these examples relates to a finalcompound of Formula (I), the pharmaceutically acceptable salts thereof,the solvates and the stereochemically isomeric forms and the tautomersthereof.

Typical examples of recipes for the formulation of the invention are asfollows:

C.1. Tablets

Active ingredient 5 to 50 mg Di calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

C.2. Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the active compounds, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 ml.

C.3. Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol inwater.

C.4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Water ad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from thescope of the invention. It will be obvious that the thus describedinvention may be varied in many ways by those skilled in the art.

1. A compound of formula (I), wherein

R¹ is selected from the group consisting of: hydrogen, hydroxy,C₁₋₄alkyl, mono- or di(C₁₋₄alkyl)amino, and Heterocyclyl¹; R² ishydrogen or C₁₋₄alkyl; R³ is selected from the group consisting of:C₁₋₄alkyl, halo, C₃₋₆cycloalkyl, mono- or di(C₁₋₄alkyl)amino, andHeterocyclyl²; R⁴ is selected from the group consisting of: hydrogen,C₁₋₆alkyl, hydroxy, and halo; Heterocyclyl¹ is selected from the groupconsisting of: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, andmorpholinyl; wherein each azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, and morpholinyl is optionally substituted with one or twosubstituents each independently selected from the group consisting of:C₁₋₄alkyl, hydroxy, halo, polyhaloC₁₋₄alkyl, C₁₋₄alkyloxycarbonyl,amino, C₁₋₄alkylaminocarbonyl, and C₁₋₄alkylsulfonyl; Heterocyclyl² isselected from the group consisting of: azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, and morpholinyl; wherein each azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl is optionallysubstituted with one or two substituents each independently selectedfrom the group consisting of: C₁₋₄alkyl, hydroxy, halo,polyhaloC₁₋₄alkyl, C₁₋₄alkyloxycarbonyl, amino,C₁₋₄alkyloxycarbonylamino, and C₁₋₄alkylsulfonyl; and Het is selectedfrom the group consisting of: furanyl, thiophenyl, pyrazolyl, oxazolyl,thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl,isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,5-naphthyridinyl,1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl,pyrido[2,3-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, 9H-purinyl,thiazolo[5,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl,oxazolo[5,4-d]pyrimidinyl, thieno[2,3-d]-pyrimidinyl, andthieno[3,2-d]pyrimidinyl; wherein each furanyl thiophenyl, pyrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, 1,5-naphthyridinyl,1,6-naphthyridinyl 1,7-naphthyridinyl, 1,8-naphthyridinyl,pyrido[2,3-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, 9H-purinyl,thiazolo[5,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl,oxazolo[5,4-d]pyrimidinyl, thieno[2,3-d]-pyrimidinyl, andthieno[3,2-d]pyrimidinyl is optionally substituted with one, two orthree substituents each independently selected from the group consistingof: halo, C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxy, amino, mono-or di(C₁₋₄alkyl)amino, hydroxycarbonyl, C₁₋₄alkyloxycarbonyl,C₁₋₄alkylsulfonylamino, aminocarbonyl, trifluoromethyl,C₁₋₄alkyloxycarbonylamino, di(C₁₋₄alkyloxycarbonyl)amino,C₁₋₄alkylsulfonylaminocarbonyl, C₁₋₄alkylaminocarbonyl,C₁₋₄alkyloxyC₁₋₆alkyloxycarbonylamino,di(C₁₋₄alkyl)aminosulfonyl-aminocarbonyl,C₃₋₆cycloalkylsulfonylaminocarbonyl, and HO—NH—(C═NH)—; and oxazolyl ortriazolyl; wherein each oxazolyl or triazolyl is optionally substitutedwith one or two C₁₋₄alkyl; and pharmaceutically acceptable saltsthereof.
 2. The compound as claimed in claim 1 wherein R¹ is hydrogen,C₁₋₄alkyl, mono- or di(C₁₋₄alkyl)amino, or Heterocyclyl¹; R² is hydrogenor C₁₋₄alkyl; R³ is C₃₋₆cycloalkyl or Heterocyclyl²; R⁴ is hydrogen;Heterocyclyl¹ is piperazinyl or morpholinyl; wherein each piperazinyl ormorpholinyl is optionally substituted with one substituent selected fromC₁₋₄alkyloxycarbonyl, C₁₋₄alkylaminocarbonyl, or C₁₋₄alkylsulfonyl;Heterocyclyl² is azetidinyl, or pyrrolidinyl; wherein each azetidinyl,or pyrrolidinyl is optionally substituted with one substituent selectedfrom hydroxy or amino; and Het is selected from quinazolinyl,pyrido[2,3-d]pyrimidinyl, thiazolo[5,4-d]-pyrimidinyl,7H-pyrrolo[2,3-d]pyrimidinyl, oxazolo[5,4-d]pyrimidinyl, orthieno[2,3-d]pyrimidinyl; wherein each quinazolinyl,pyrido[2,3-d]pyrimidinyl, thiazolo[5,4-d]-pyrimidinyl,7H-pyrrolo[2,3-d]pyrimidinyl, oxazolo[5,4-d]pyrimidinyl, orthieno[2,3-d]pyrimidinyl is optionally substituted with one, two orthree substituents each independently selected from halo, C₁₋₄alkyl,C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxy, hydroxycarbonyl,C₁₋₄alkyloxycarbonyl, C₁₋₄alkylsulfonylamino, aminocarbonyl,trifluoromethyl, C₁₋₄alkyloxy-carbonylamino,di(C₁₋₄alkyloxycarbonyl)amino, C₁₋₄alkylsulfonylamino-carbonyl,C₁₋₄alkylaminocarbonyl, C₁₋₄alkyloxyC₁₋₆alkyloxycarbonylamino,di(C₁₋₄alkyl)aminosulfonylaminocarbonyl,C₃₋₆cycloalkylsulfonylamino-carbonyl, and HO—NH—(C═NH)—; and oxazolyl ortriazolyl; wherein each oxazolyl or triazolyl is optionally substitutedwith one or two C₁₋₄alkyl.
 3. The compound as claimed in claim 1 whereinR¹ is Heterocyclyl¹, R² is hydrogen, and R³ is Heterocyclyl².
 4. Thecompound as claimed in claim 1 wherein R¹ is hydrogen, R² is C₁₋₄alkyl,and R³ is Heterocyclyl².
 5. The compound as claimed in claim 1 whereinR¹ is hydrogen, R² is hydrogen, and R³ is Heterocyclyl².
 6. The compoundas claimed in claim 1 wherein R¹ is C₁₋₄alkyl, R² is hydrogen, and R³ isHeterocyclyl².
 7. The compound as claimed in claim 1 wherein R¹ ishydrogen, R² is hydrogen, and R³ is C₁₋₄alkyl.
 8. The compound asclaimed in claim 1 wherein R¹ is hydrogen, R² is hydrogen, and R³ isC₃₋₆cycloalkyl.
 9. The compound as claimed in claim 1 wherein Het isquinazolinyl.
 10. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically active amountof a compound as claimed in claim 1 or a pharmaceutically acceptablesalt thereof.
 11. A process for preparing a pharmaceutical compositionas claimed in claim 8 wherein a therapeutically active amount of acompound as claimed in claim 1 or a pharmaceutically acceptable saltthereof is mixed with a pharmaceutically acceptable carrier. 12.(canceled)
 13. A method of treating a respiratory syncytial virusinfection in a patient, comprising administering the compound as claimedin claim 1 or a pharmaceutically acceptable salt thereof to saidpatient.
 14. A compound selected from the group consisting of:4-(5-(Azetidin-1-yl)-2-(1-(6-chloroquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;(S)-4-(5-(Azetidin-1-yl)-2-(1-(6-chloroquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;(R)-4-(5-(Azetidin-1-yl)-2-(1-(6-chloroquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;4-(5-(Azetidin-1-yl)-2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;4-(5-(Azetidin-1-yl)-2-(1-(2-chloro-6-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;N-(4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2yl)-piperidin-1-yl)-6-methylquinazolin-2-yl)methanesulfonamide;(R)—N-(4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-6-methylquinazolin-2-yl)methanesulfonamide;(S)—N-(4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-6-methylquinazolin-2-yl)methanesulfonamide;N-(4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2yl)piperidin-1-yl)-5-methylquinazolin-2-yl)methanesulfonamide;N-(4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2yl)piperidin-1-yl)quinazolin-2-yl)methanesulfonamide;4-(2-(5-(Azetidin-1-yl)-6-methylpyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-6-methylquinazoline;1-(6-Methyl-2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-ol;1-(6-Methyl-2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo-[1,5-a]pyrimidin-5-yl)azetidin-3-amine;2-Methoxyethyl4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]-pyrimidin-2-yl)piperidin-1-yl)-6-morpholinoquinazolin-2-ylcarbamate;4-(5-(Azetidin-1-yl)-2-(1-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;4-(5-(Azetidin-1-yl)-2-(1-(2-ethoxypyrido[2,3-d]pyrimidin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;4-(5-(Azetidin-1-yl)-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;(R)-4-(5-(Azetidin-1-yl)-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;(S)-4-(5-(Azetidin-1-yl)-2-(1-(5methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;4-(5-(Azetidin-1-yl)-2-(1-(2-methylthiazolo[5,4-d]pyrimidin-7-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;4-(2-(5-(Azetidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-6-methylquinazoline;4-(2-(5-(Azetidin-1-yl)-6-methyl-7-(piperidin-1-yl)pyrazolo[1,5-a]-pyrimidin-2-yl)piperidin-1-yl)-6-methylquinazoline;1-(6-Methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo-[1,5-a]pyrimidin-5-yl)azetidin-3-ol;(R)-1-(6-Methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]-pyrimidin-5-yl)azetidin-3-ol;(S)-1-(6-Methyl-2-(1-(5-methylquinazolin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-ol;1-(6-Methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo-[1,5-a]pyrimidin-5-yl)azetidin-3-amine;1-(2-(1-(2,5-Dimethylquinazolin-4-yl)piperidin-2-yl)-6-methyl-pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-amine;Dimethyl(4-{2-[5-(azetidin-1-yl)-7-(morpholin-4-yl)pyrazolo[1,5-a]-pyrimidin-2-yl]piperidin-1-yl}-5-methylquinazolin-2-yl)imidodicarbonate;Methyl(4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]-pyrimidin-2-yl)piperidin-1-yl)-5-methylquinazolin-2-yl)carbamate;4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-N-hydroxy-5-methylquinazoline-2-carboximidamide;4-(5-(Azetidin-1-yl)-2-(1-(2-ethoxy-5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;(S)—N-(4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-6-chloroquinazolin-2-yl)methanesulfonamide;(S)—N-(4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]-pyrimidin-2-yl)piperidin-1-yl)-6-chloroquinazolin-2-yl)methanesulfonamide;(R)—N-(4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]-pyrimidin-2-yl)piperidin-1-yl)-6-chloroquinazolin-2-yl)methanesulfonamide;4-(5-(Azetidin-1-yl)-2-(1-(5-chloroquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-N—(N,N-dimethylsulfamoyl)quinazoline-2-carboxamide;1-(2-(1-(2,5-Dimethylquinazolin-4-yl)piperidin-2-yl)-6-methyl-pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-ol;(S)-1-(2-(1-(2,5-Dimethylquinazolin-4-yl)piperidin-2-yl)-6-methyl-pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-ol;(R)-1-(2-(1-(2,5-Dimethylquinazolin-4-yl)piperidin-2-yl)-6-methyl-pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-ol;1-(2-(1-(2-Chloro-5-methylquinazolin-4-yl)piperidin-2-yl)-6-methylpyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-ol;N-(4-(2-(5-(3-Hydroxyazetidin-1-yl)-6-methylpyrazolo[1,5-a]-pyrimidin-2-yl)piperidin-1-yl)-5-methylquinazolin-2-yl)methanesulfonamide;1-(2-(1-(2,6-Dimethylquinazolin-4-yl)piperidin-2-yl)-6-methyl-pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-ol;(S)-1-(2-(1-(2,6-Dimethylquinazolin-4-yl)piperidin-2-yl)-6-methyl-pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-ol;(R)-1-(2-(1-(2,6-Dimethyl-quinazolin-4-yl)piperidin-2-yl)-6-methylpyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-ol;4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-5-methylquinazolin-2-ol;4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-5-methylquinazoline-2-carboxamide;4-(5-Cyclopropyl-6-methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;(3S)-1-(6-Methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-3-amine;(3S)-1-(2-(1-(6-Methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-3-amine;(S)-1-(2-((R)-1-(6-Methylquinazolin-4-yl)piperidin-2-yl)pyrazolo-[1,5a]-pyrimidin-5-yl)pyrrolidin-3-amine;(S)-1-(2-((S)-1-(6-Methylquinazolin-4-yl)piperidin-2-yl)pyrazolo-[1,5a]-pyrimidin-5-yl)pyrrolidin-3-amine; tert-Butyl4-(5-(azetidin-1-yl)-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)piperazine-1-carboxylate;4-(2-(5-(Azetidin-1-yl)-7-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-2yl)-piperidin-1-yl)-5-methylquinazoline;4-(5-(Azetidin-1-yl)-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)-N-isopropylpiperazine-1-carboxamide;4-(2-(5-(Azetidin-1-yl)-7-(4-(methylsulfonyl)piperazin-1-yl)pyrazolo-[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-5-methylquinazoline;7-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-2-methyloxazolo[5,4-d]pyrimidine;4-(5-(Azetidin-1-yl)-2-(1-(6-methyl-2-(methylthio)quinazolin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;4-(5-(Azetidin-1-yl)-2-(1-(5-ethylquinazolin-4-yl)piperidin-2-yl)-pyrarazolo[1,5-a]pyrimidin-7-yl)morpholine;4-(5-(Azetidin-1-yl)-2-(1-(5,7-dimethylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;4-(5-(Azetidin-1-yl)-2-(1-(5-fluoroquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;4-(5-(Azetidin-1-yl)-2-(1-(5-ethoxyquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;4-(5-(Azetidin-1-yl)-2-(1-(5-(trifluoromethyl)quinazolin-4-yl)piperidin-2-yl)pyrarazolo[1,5-a]pyrimidin-7-yl)morpholine;4-(5-(Azetidin-1-yl)-2-(1-(6-ethyl-5-methylquinazolin-4-yl)piperidin-2yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;4-(5-(Azetidin-1-yl)-2-(1-(5,6-dimethylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;7-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-2-methyloxazolo[5,4-d]pyrimidine;4-(5-(Azetidin-1-yl)-2-(1-(5,8-dimethylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;Methyl4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-5-methylquinazoline-2-carboxylate;4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-5-methylquinazoline-2-carboxylicacid;4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-5-methyl-N-(methylsulfonyl)quinazoline-2-carboxamide;4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-N,5-dimethylquinazoline-2-carboxamide;4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-N-(cyclopropylsulfonyl)-5-methylquinazoline-2-carboxamide;4-(5-(Azetidin-1-yl)-2-(1-(2-(isoxazol-4-yl)-5-methylquinazolin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;4-(5-(Azetidin-1-yl)-2-(1-(2-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-methyl-quinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;and4-(5-(Azetidin-1-yl)-2-(1-(5-methoxyquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;and pharmaceutically acceptable salts thereof.
 15. A pharmaceuticalcomposition, comprising (a) a therapeutically active amount of at leastone compound of claim 14 or a pharmaceutically acceptable salt thereof;and (b) at least one pharmaceutically acceptable carrier.
 16. A methodof treatment of a subject suffering from a respiratory syncytial virusinfection, comprising administering to the subject a therapeuticallyactive amount of a compound as claimed in claim 14 or a pharmaceuticallyacceptable salt thereof.